仔猪肝脏糖皮质激素受体基因表达的品种差异及其转录调控机制
摘要
糖皮质激素(glucocorticoid)通过糖皮质激素受体(glucocorticoid receptor, GR)调节机体各方面生理代谢过程。中国地方猪种二花脸猪与外来猪种大白猪相比,血液皮质醇水平和肝脏GR mRNA和蛋白水平存在明显的品种差异。我们实验室以往的研究对中国地方猪种和外来猪种皮质醇合成通路进行了探讨,但是不同品种间肝脏GRmRNA差异表达的机理却不清楚,加上猪GR基因启动子序列一直没有确认,使得对猪GR基因转录调控的研究更加困难。本研究克隆了猪GR基因的近端启动子序列,鉴定了GR基因外显子Ⅰ的七个可变剪切变体,并对每个变体5’和3’在基因组上进行了定位。比较了新生大白猪和二花脸猪肝脏GR mRNA及其外显子Ⅰ可变剪切变体的表达,发现变体1-4和1-5在大白猪表达显著高于二花脸猪。对肝脏GR启动子甲基化分析表明GR启动子甲基化程度在大白猪和二花脸猪上并没有差异,转录因子CREB (cAMP responsive element-binding protein)和GR参与了新生时GR变体1-4和1-5的转录调控,导致大白猪总GR mRNA表达高于二花脸猪。断奶前仔猪GRmRNA出现相反的趋势,大白猪GR外显子Ⅰ变体1-9,10和总GR mRNA表达低于二花脸猪,Sp1(specificity protein1)和p53参与了变体1-9,10的转录调控。体外实验用HepG2细胞加上p53通路的激活剂药物Doxorubicin (Dox)处理后,GR mRNA(?)即发生相应的改变,进一步证明p53通过Sp1调控了GR mRNA的转录。
1猪GR基因近端启动子序列与选择性外显子Ⅰ的确定
通过比对已经发表的人GR(AY436590X大鼠GR(AJ271870)、小鼠GR(X66367)基因启动子序列,选取高度同源区域和已知的猪GR cDNA (AY779185.1)序列作为探针,筛选到猪基因细菌人工染色体(BAC)阳性克隆,序号为CH242-105G5,此克隆委托Sanger公司测序得到猪GR基因完整序列,NCBI登记号为CU928713。对猪GR基因近端启动子序列和人、大鼠和小鼠GR外显子Ⅰ可变剪切变体进行同源比对,分别在外显子Ⅰ不同变体的同源保守区和外显子2上设计上游和下游引物。PCR扩增后产物经过电泳、切胶、纯化后导入pMDH18-T Vector载体克隆测序,确定猪GR近端外显子Ⅰ存在7个变体,即变体1-4,1-5,1-6,1-7,1-8,1-9,10,1-11,并且对这7个变体碱基序列进行了鉴定。由于七个外显子末端都是连接在相同剪切位点即外显子2上,因此可对不同变体3’边界进行定位,另外根据猪GR外显子Ⅰ和人、大鼠GR外显子同源性比对结果,确定了外显子Ⅰ不同变体5’边界。将猪GR外显子Ⅰ变体与人、大鼠、小鼠对应的变体进行序列同源性分析表明,与人GR外显子Ⅰ变体序列相比,猪GR序列同源性比大鼠、小鼠的同源性要高。猪GR启动子及其变体序列确定的为下一步对猪GR基因在不同组织表达及其组织特异性调控提供了基础。
2猪肝脏GR mRNA变体表达的品种差异与GR启动-γ-甲基化分析
选取6头初生的雄性大白猪和二花脸猪,屠宰取肝脏样品提取总RNA并反转成cDNA。用Real time PCR方法对GR外显子Ⅰ近端7个变体即1-4,1-5,1-6,1-7,1-8,1-9,10,1-11mRNA表达丰度进行了品种间比较。结果显示新生大白猪肝脏总GR mRNA和变体1-4,1-5mRNA表达均显著高于二花脸猪(P<0.05)。由于猪GR近端启动子富含CpG位点,且被包含在一个大的CpG岛内,我们推测变体1-4和1-5转录差异是否由启动子甲基化水平不同而引起的。因此将肝脏DNA采用亚硫酸盐处理,并结合Sequenom's Massarray Array方法对GR启动子甲基化水平进行了分析。结果表明,GR启动子总的甲基化水平没有差异,同时转录有差异的1-4和1-5变体对应的启动子甲基化也不存在差异。整个GR启动子内某几个位点甲基化水平有差异,生物信息学分析这些甲基化位点位于某些转录因子位点结合处,但是甲基化的差异并没有影响到相应变体的表达,提示不同品种猪肝脏GR mRNA差异表达可能主要由转录因子调控引起的。
3初生仔猪肝脏GR表达的品种差异及其转录调控
新生时GR启动子甲基化可能没有参与品种间GR mRNA的转录调控,于是我们从转录因子方面对新生时期大白猪和二花脸猪GR基因的转录调控进行了研究。生物信息学分析显示GR1-5启动子上含有CREB, Spl. GR等反式因子结合位点,1-4启动子上除了以上转录因子外还有两个YY1(Ying Yang1)结合位点。Western blot分析显示新生时肝脏核蛋白Spl,p-CREB, GR均是大白猪显著高于二花脸猪(P<0.05),YY1在肝脏核蛋白表达量以及结合在启动子1-4上都没有差异,结合在GR启动子1-4上的p-CREB在大白猪大于二花脸猪,相反大白猪猪结合在启动子1-4,1-5上GR明显低于二花脸猪,同时结合在启动子1-4和1-5上乙酰化的组蛋白大白猪也比二花脸猪高(P<0.05,或P<0.01)。以上结果提示, p-CREB参与了GR转录正向调控,而GR对自身转录形成负调控。新生时大白猪和二花脸猪品种间GR mRNA差异化的转录是由结合在启动子上的不同的p-CREB和GR以及乙酰化组蛋白而造成的。
4断奶前仔猪肝脏GR表达的品种差异及其转录调控
我们对断奶前大白猪和二花脸肝脏GR mRNA及其外显子Ⅰ变体进行研究,发现大白猪总GR mRNA表达显著低于二花脸猪,对GR基因外显子Ⅰ近端的7个变体进行分析,只有变体1-9,10mRNA的表达在两品种间有差异,其他变体没有差异。变体1-9,10在7个GR外显子Ⅰ的变体中所占比例最大,表明GR变体1-9,10的差异是导致总GR差异的主要原因。研究发现肝脏核蛋白中Sp1的水平在大白猪显著高于二花脸猪(P<0.05),但是结合在GR启动子1-9,10上Sp1水平却是大白猪低于二花脸猪(P<0.05),同时大白猪结合在GR启动子1-9,10上乙酰化组蛋白比二花脸猪要少。用免疫共沉淀方法发现肝脏核蛋白中转录因子Sp1可以结合p53,反之亦然。另外我们发现肝脏p53mRNA与GR mRNA呈显著正相关(P=0.001),为了进一步探讨p53参与GR转录调控可能的机制,我们体外培养了HepG2细胞,用p53通路的激活剂Doxorubicin (DOX)对细胞进行了处理。实验表明HepG2细胞培养液中加入100nmol/L Dox显著提高了细胞p53和GR蛋白表达(P<0.05,或P<0.01),同时GR变体1-9,10表达也显著提高。将猪GR基因1-9,10启动子序列(-3149～-2724bp)构建的荧光素酶报告系统瞬时转染导入HepG2细胞,分别用10nmol/L和100nmol/LDox处理细胞,100nmol/L浓度的Dox处理导致荧光素酶报告体系活性明显升高(P<0.01)。综合以上体内和体外结果提示,Sp1直接参与了肝脏总GR mRNA以及GR变体1-9,10mRNA的转录调控,p53通过Sp1以蛋白-蛋白相互作用方式间接调控了GR转录。
Glucocorticoids regulate an array of physiological functions by binding to the ubiquitously expressed glucocorticoid receptor (GR). Chinese indigenous pig, Erhualian(EHL), showed more cortisol in blood and expressed higher GR mRNA in liver compared with Large White pig(LW). Previous study in our laboratory have studied cortisol synthesis pathway in LW and EHL piglets, however different GR mRNA expression in liver and investigation into the breed-dependent GR transcriptional regulation is hampered by lacking porcine GR promoter information. In this study, we cloned and sequenced proximal promoter of pig GR gene and detected seven alternative first exons of GR gene.5'and3' boundary of alternative first eoxns were determined on genomic position. We studied GR mRNA and GR alternative first exons in liver of newborn piglets, and found exon1-4and1-5were significantly higher in LW than that in EHL piglets, methylation of GR promoter had no difference between two breeds of piglets. Trans-acting factors, p-CREB and GR took part in transcriptional regulation of exon1-4and exon1-5and deduced different expression of total GR mRNA. However, hepatic GR mRNA and exon1-9,10in LW were significantly lower than that in EHL in preweaning piglets, Spl and p53were involved in exon1-9,10transcriptional regulation. In vitro experiment we used doxorubicin (DOX) to activate p53and found that p53protein in HepG2cells increased concominant with enhanced GR protein. In vivo and in vitro studies proved that Sp1directedly regulated GR exon1-9,10transcription, while p53regulated GR mRNA through protein-protein mechanism with Spl.
1Sequence of proximal promoter of glucocorticoid receptor and first alternative exons
We first compared the published GR promoter sequences of human (AY436590), rat (AJ271870) and mouse (X66367), and identified the highly conserved regions. Using these highly conserved sequences and the porcine GR cDNA sequence (AY779185.1) as probes, we screened the porcine bacterial artificial chromosome(BAC) library and hit a positive clone (CH242-105G5). The BAC clone was then priority sequenced by the Sanger Institute upon our request.Within the complete sequence (CU928713) of the clone, we verified, by sequencing the overlapping PCR products amplified from porcine genomic DNA extracted from liver, a5300bp59flanking sequence of porcine GR exon2. We designed the upstream primers according to the sequence homology of pig with human and rat,which were located in various first exons, while the downstream primers were located in coding region of exon2. Seven pairs of primers were used to amplify the alternative first exons with cDNAs, then the PCR products were detected in gel and the expected bands were cut out and cloned into the pMDH18-T Vector, after that the clones were sequenced. All the alternative first exons were spliced to the same nocleotide sequence located in exon2, thus the3'end of the first exons were determined. The5'boundaries were identified by bioinformatic prediction referring to the5'boundary sequences of the first exons in human and rat GR. Homologous analysis of GR gene of pig, human, rat and mouse, revealed that pig GR sequence shared more homologous with human than rat and mouse. Sequence of pig GR gene provided basis for further study of pig GR gene transcription and expression in different tissue and different breeds of pigs.
2Analysis of methylaiton of promoter of GR in liver of LW and EHL pigs
In this study, we used six newborn male LW and EHL pig and studied total GR mRNA and seven alternative5'-untranslated first exons1-4,1-5,1-6,1-7,1-8,1-9,10and1-11of GR gene. Among all these GR mRNA variants, exons1-4and1-5, as well as the total GR were expressed in a breed-dependent manner in the liver, newborn piglets of LW showing significantly (P<0.05) higher expression compared with EHL. Since promoter of GR gene are GC rich and are located in a CpG island, it was speculated that methylation of promoter will account for GR1-4and1-5mRNA different expression. Genomic DNA of liver was treated with bisulfite and methylation of promoter was analysed by the method of Mass-array ARRAY. Result showed that overall average methylaiton of GR promoter and promoter of exon1-4and1-5had no difference between two breeds of piglets, methylation of several sites of CpG island had difference, bioinformatics analysis revealed that these CpG positions were located in binding sites for transcription factors, however methylation of these positions had on effect on exon transcription, implying that mechanism of transcription regulation involved in trans-acting factors will account for different GR mRNA expression in liver.
3Breed-dependent transcriptional regulation of5'-untranslated GR Exon I mRNA variants in the liver of newborn piglets
Methylation of promoter of GR gene were not the reason for different GR mRNA transcription in two breeds of newborn piglets, therefore we studied GR transcription regulation in aspect of trans-acting factors. Bioimformatics anslysis revealed that CREB, Spl and GR harbored binding sites on promoter1-5of GR gene, what is more, promoter1-4harbored two YY1(Ying yang1) binding sites. Nuclear content of Spl, p-CREB and GR in the liver was significantly higher in LW piglets(P<0.05), associated with enhanced binding of p-CREB, as well as higher level of histone H3acetylation in1-4and1-5promoters^<0.05, or P<0.01). In contrast, GR binding to promoters of exons1-4and1-5was significantly diminished in LW piglets, implicating the presence of negative GREs. YY1had no difference in hepatic nuclear content and showed no binding difference to promoter1-4. These results indicated p-CREB and GR were involved in positive and negative transcriptional regulation of GR mRNA, respectively. The difference in the hepatic expression of GR transcript variants between two breeds of pigs was determined, at least partly, by the disparity in the binding of transcription factors and the enrichment of histone H3acetylation to the promoters.
4Breed-dependent transcriptional regulation of5'-untranslated GR Exon I mRNA variants in the liver of preweaning piglets
In this study we studied hepatic GR mRNA expression in preweaning piglets, and found that LW pig express lower GR mRNA than EHL piglets. We studied seven GR alternative first exons and found1-9,10showed breed depended difference, while other exons had no difference. Exon1-9,10was the most abundant expression in GR first exons and deduced total GR mRNA difference in two breeds of piglets. Nuclear content of Sp1in the liver was significantly (P<0.05) higher in LW piglets, however, LW piglets showed decreased binding of Spl to promoter1-9,10, as well as lower level of histone H3acetylation in1-9,10promoter. Co-Immunoprecipitation analysis revealed that Sp1interacted with p53, and vice versa. Hepatic p53mRNA was significantly correlation with GR mRNA(P=0.001), in order to study the mechanism of p53regulating transcription of GR mRNA, we cultured HepG2cell. Dox was added to the culture and activated p53pathway, it significantly increased p53and GR protein (concominant with enhanced GR1-9,10mRNA expression(P<0.05). Promoter-luciferase reporter gene construct containing the sequence between-3149and-2724of pig GR gene (located in promoter1-9,10) was generated, construct was transiently transfected into HepG2cells,100nmol/L DOX significantly increased promoter luciferase activity(P<0.01). The present study showed that Sp1directedly increased transcription of GR, while p53increased GR transcription by interaction with Spl protein.
1猪GR基因近端启动子序列与选择性外显子Ⅰ的确定
通过比对已经发表的人GR(AY436590X大鼠GR(AJ271870)、小鼠GR(X66367)基因启动子序列,选取高度同源区域和已知的猪GR cDNA (AY779185.1)序列作为探针,筛选到猪基因细菌人工染色体(BAC)阳性克隆,序号为CH242-105G5,此克隆委托Sanger公司测序得到猪GR基因完整序列,NCBI登记号为CU928713。对猪GR基因近端启动子序列和人、大鼠和小鼠GR外显子Ⅰ可变剪切变体进行同源比对,分别在外显子Ⅰ不同变体的同源保守区和外显子2上设计上游和下游引物。PCR扩增后产物经过电泳、切胶、纯化后导入pMDH18-T Vector载体克隆测序,确定猪GR近端外显子Ⅰ存在7个变体,即变体1-4,1-5,1-6,1-7,1-8,1-9,10,1-11,并且对这7个变体碱基序列进行了鉴定。由于七个外显子末端都是连接在相同剪切位点即外显子2上,因此可对不同变体3’边界进行定位,另外根据猪GR外显子Ⅰ和人、大鼠GR外显子同源性比对结果,确定了外显子Ⅰ不同变体5’边界。将猪GR外显子Ⅰ变体与人、大鼠、小鼠对应的变体进行序列同源性分析表明,与人GR外显子Ⅰ变体序列相比,猪GR序列同源性比大鼠、小鼠的同源性要高。猪GR启动子及其变体序列确定的为下一步对猪GR基因在不同组织表达及其组织特异性调控提供了基础。
2猪肝脏GR mRNA变体表达的品种差异与GR启动-γ-甲基化分析
选取6头初生的雄性大白猪和二花脸猪,屠宰取肝脏样品提取总RNA并反转成cDNA。用Real time PCR方法对GR外显子Ⅰ近端7个变体即1-4,1-5,1-6,1-7,1-8,1-9,10,1-11mRNA表达丰度进行了品种间比较。结果显示新生大白猪肝脏总GR mRNA和变体1-4,1-5mRNA表达均显著高于二花脸猪(P<0.05)。由于猪GR近端启动子富含CpG位点,且被包含在一个大的CpG岛内,我们推测变体1-4和1-5转录差异是否由启动子甲基化水平不同而引起的。因此将肝脏DNA采用亚硫酸盐处理,并结合Sequenom's Massarray Array方法对GR启动子甲基化水平进行了分析。结果表明,GR启动子总的甲基化水平没有差异,同时转录有差异的1-4和1-5变体对应的启动子甲基化也不存在差异。整个GR启动子内某几个位点甲基化水平有差异,生物信息学分析这些甲基化位点位于某些转录因子位点结合处,但是甲基化的差异并没有影响到相应变体的表达,提示不同品种猪肝脏GR mRNA差异表达可能主要由转录因子调控引起的。
3初生仔猪肝脏GR表达的品种差异及其转录调控
新生时GR启动子甲基化可能没有参与品种间GR mRNA的转录调控,于是我们从转录因子方面对新生时期大白猪和二花脸猪GR基因的转录调控进行了研究。生物信息学分析显示GR1-5启动子上含有CREB, Spl. GR等反式因子结合位点,1-4启动子上除了以上转录因子外还有两个YY1(Ying Yang1)结合位点。Western blot分析显示新生时肝脏核蛋白Spl,p-CREB, GR均是大白猪显著高于二花脸猪(P<0.05),YY1在肝脏核蛋白表达量以及结合在启动子1-4上都没有差异,结合在GR启动子1-4上的p-CREB在大白猪大于二花脸猪,相反大白猪猪结合在启动子1-4,1-5上GR明显低于二花脸猪,同时结合在启动子1-4和1-5上乙酰化的组蛋白大白猪也比二花脸猪高(P<0.05,或P<0.01)。以上结果提示, p-CREB参与了GR转录正向调控,而GR对自身转录形成负调控。新生时大白猪和二花脸猪品种间GR mRNA差异化的转录是由结合在启动子上的不同的p-CREB和GR以及乙酰化组蛋白而造成的。
4断奶前仔猪肝脏GR表达的品种差异及其转录调控
我们对断奶前大白猪和二花脸肝脏GR mRNA及其外显子Ⅰ变体进行研究,发现大白猪总GR mRNA表达显著低于二花脸猪,对GR基因外显子Ⅰ近端的7个变体进行分析,只有变体1-9,10mRNA的表达在两品种间有差异,其他变体没有差异。变体1-9,10在7个GR外显子Ⅰ的变体中所占比例最大,表明GR变体1-9,10的差异是导致总GR差异的主要原因。研究发现肝脏核蛋白中Sp1的水平在大白猪显著高于二花脸猪(P<0.05),但是结合在GR启动子1-9,10上Sp1水平却是大白猪低于二花脸猪(P<0.05),同时大白猪结合在GR启动子1-9,10上乙酰化组蛋白比二花脸猪要少。用免疫共沉淀方法发现肝脏核蛋白中转录因子Sp1可以结合p53,反之亦然。另外我们发现肝脏p53mRNA与GR mRNA呈显著正相关(P=0.001),为了进一步探讨p53参与GR转录调控可能的机制,我们体外培养了HepG2细胞,用p53通路的激活剂Doxorubicin (DOX)对细胞进行了处理。实验表明HepG2细胞培养液中加入100nmol/L Dox显著提高了细胞p53和GR蛋白表达(P<0.05,或P<0.01),同时GR变体1-9,10表达也显著提高。将猪GR基因1-9,10启动子序列(-3149～-2724bp)构建的荧光素酶报告系统瞬时转染导入HepG2细胞,分别用10nmol/L和100nmol/LDox处理细胞,100nmol/L浓度的Dox处理导致荧光素酶报告体系活性明显升高(P<0.01)。综合以上体内和体外结果提示,Sp1直接参与了肝脏总GR mRNA以及GR变体1-9,10mRNA的转录调控,p53通过Sp1以蛋白-蛋白相互作用方式间接调控了GR转录。
Glucocorticoids regulate an array of physiological functions by binding to the ubiquitously expressed glucocorticoid receptor (GR). Chinese indigenous pig, Erhualian(EHL), showed more cortisol in blood and expressed higher GR mRNA in liver compared with Large White pig(LW). Previous study in our laboratory have studied cortisol synthesis pathway in LW and EHL piglets, however different GR mRNA expression in liver and investigation into the breed-dependent GR transcriptional regulation is hampered by lacking porcine GR promoter information. In this study, we cloned and sequenced proximal promoter of pig GR gene and detected seven alternative first exons of GR gene.5'and3' boundary of alternative first eoxns were determined on genomic position. We studied GR mRNA and GR alternative first exons in liver of newborn piglets, and found exon1-4and1-5were significantly higher in LW than that in EHL piglets, methylation of GR promoter had no difference between two breeds of piglets. Trans-acting factors, p-CREB and GR took part in transcriptional regulation of exon1-4and exon1-5and deduced different expression of total GR mRNA. However, hepatic GR mRNA and exon1-9,10in LW were significantly lower than that in EHL in preweaning piglets, Spl and p53were involved in exon1-9,10transcriptional regulation. In vitro experiment we used doxorubicin (DOX) to activate p53and found that p53protein in HepG2cells increased concominant with enhanced GR protein. In vivo and in vitro studies proved that Sp1directedly regulated GR exon1-9,10transcription, while p53regulated GR mRNA through protein-protein mechanism with Spl.
1Sequence of proximal promoter of glucocorticoid receptor and first alternative exons
We first compared the published GR promoter sequences of human (AY436590), rat (AJ271870) and mouse (X66367), and identified the highly conserved regions. Using these highly conserved sequences and the porcine GR cDNA sequence (AY779185.1) as probes, we screened the porcine bacterial artificial chromosome(BAC) library and hit a positive clone (CH242-105G5). The BAC clone was then priority sequenced by the Sanger Institute upon our request.Within the complete sequence (CU928713) of the clone, we verified, by sequencing the overlapping PCR products amplified from porcine genomic DNA extracted from liver, a5300bp59flanking sequence of porcine GR exon2. We designed the upstream primers according to the sequence homology of pig with human and rat,which were located in various first exons, while the downstream primers were located in coding region of exon2. Seven pairs of primers were used to amplify the alternative first exons with cDNAs, then the PCR products were detected in gel and the expected bands were cut out and cloned into the pMDH18-T Vector, after that the clones were sequenced. All the alternative first exons were spliced to the same nocleotide sequence located in exon2, thus the3'end of the first exons were determined. The5'boundaries were identified by bioinformatic prediction referring to the5'boundary sequences of the first exons in human and rat GR. Homologous analysis of GR gene of pig, human, rat and mouse, revealed that pig GR sequence shared more homologous with human than rat and mouse. Sequence of pig GR gene provided basis for further study of pig GR gene transcription and expression in different tissue and different breeds of pigs.
2Analysis of methylaiton of promoter of GR in liver of LW and EHL pigs
In this study, we used six newborn male LW and EHL pig and studied total GR mRNA and seven alternative5'-untranslated first exons1-4,1-5,1-6,1-7,1-8,1-9,10and1-11of GR gene. Among all these GR mRNA variants, exons1-4and1-5, as well as the total GR were expressed in a breed-dependent manner in the liver, newborn piglets of LW showing significantly (P<0.05) higher expression compared with EHL. Since promoter of GR gene are GC rich and are located in a CpG island, it was speculated that methylation of promoter will account for GR1-4and1-5mRNA different expression. Genomic DNA of liver was treated with bisulfite and methylation of promoter was analysed by the method of Mass-array ARRAY. Result showed that overall average methylaiton of GR promoter and promoter of exon1-4and1-5had no difference between two breeds of piglets, methylation of several sites of CpG island had difference, bioinformatics analysis revealed that these CpG positions were located in binding sites for transcription factors, however methylation of these positions had on effect on exon transcription, implying that mechanism of transcription regulation involved in trans-acting factors will account for different GR mRNA expression in liver.
3Breed-dependent transcriptional regulation of5'-untranslated GR Exon I mRNA variants in the liver of newborn piglets
Methylation of promoter of GR gene were not the reason for different GR mRNA transcription in two breeds of newborn piglets, therefore we studied GR transcription regulation in aspect of trans-acting factors. Bioimformatics anslysis revealed that CREB, Spl and GR harbored binding sites on promoter1-5of GR gene, what is more, promoter1-4harbored two YY1(Ying yang1) binding sites. Nuclear content of Spl, p-CREB and GR in the liver was significantly higher in LW piglets(P<0.05), associated with enhanced binding of p-CREB, as well as higher level of histone H3acetylation in1-4and1-5promoters^<0.05, or P<0.01). In contrast, GR binding to promoters of exons1-4and1-5was significantly diminished in LW piglets, implicating the presence of negative GREs. YY1had no difference in hepatic nuclear content and showed no binding difference to promoter1-4. These results indicated p-CREB and GR were involved in positive and negative transcriptional regulation of GR mRNA, respectively. The difference in the hepatic expression of GR transcript variants between two breeds of pigs was determined, at least partly, by the disparity in the binding of transcription factors and the enrichment of histone H3acetylation to the promoters.
4Breed-dependent transcriptional regulation of5'-untranslated GR Exon I mRNA variants in the liver of preweaning piglets
In this study we studied hepatic GR mRNA expression in preweaning piglets, and found that LW pig express lower GR mRNA than EHL piglets. We studied seven GR alternative first exons and found1-9,10showed breed depended difference, while other exons had no difference. Exon1-9,10was the most abundant expression in GR first exons and deduced total GR mRNA difference in two breeds of piglets. Nuclear content of Sp1in the liver was significantly (P<0.05) higher in LW piglets, however, LW piglets showed decreased binding of Spl to promoter1-9,10, as well as lower level of histone H3acetylation in1-9,10promoter. Co-Immunoprecipitation analysis revealed that Sp1interacted with p53, and vice versa. Hepatic p53mRNA was significantly correlation with GR mRNA(P=0.001), in order to study the mechanism of p53regulating transcription of GR mRNA, we cultured HepG2cell. Dox was added to the culture and activated p53pathway, it significantly increased p53and GR protein (concominant with enhanced GR1-9,10mRNA expression(P<0.05). Promoter-luciferase reporter gene construct containing the sequence between-3149and-2724of pig GR gene (located in promoter1-9,10) was generated, construct was transiently transfected into HepG2cells,100nmol/L DOX significantly increased promoter luciferase activity(P<0.01). The present study showed that Sp1directedly increased transcription of GR, while p53increased GR transcription by interaction with Spl protein.
引文
[1]Makino S, Smith M A, Gold P W. Increased expression of corticotropin-releasing hormone and vasopressin messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus during repeated stress:association with reduction in glucocorticoid receptor mRNA levels[J]. Endocrinology,1995,136(8):3299-3309.
[2]Whitnall M. H. Regulation of the hypothalamic corticotropin-releasing hormone neurosecretory system[J]. Prog Neurobiol,1993,40(5):573-629.
[3]Herman J. P., Cullinan W. E., Watson S. J. Involvement of the bed nucleus of the stria terminalis in tonic regulation of paraventricular hypothalamic CRH and AVP mRNA expression[J]. J Neuroendocrinol,1994,6(4):433-442.
[4]Henry James. Biological basis of the stress response[J]. Integrative Physiological and Behavioral Science,1992,27(1):66-83.
[5]Kemeny Margaret E. The Psychobiology of Stress[J]. Current Directions in Psychological Science, 2003,12(4):124-129.
[6]Chrousos George P., Gold Philip W. A Healthy Body in a Healthy Mind—and Vice Versa—the Damaging Power of "Uncontrollable" Stress[J]. Journal of Clinical Endocrinology & Metabolism, 1998,83(6):1842-1845.
[7]Talge Nicole M., Neal Charles, Glover Vivette, et al. Antenatal maternal stress and long-term effects on child neurodevelopment:how and why?[J]. Journal of Child Psychology and Psychiatry, 2007,48(3-4):245-261.
[8]Jacobson L., Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis[J]. Endocr Rev,1991,12(2):118-134.
[9]de Kloet E. R., Reul J. M. H. M., Sutanto W. Corticosteroids and the brain[J]. The Journal of Steroid Biochemistry and Molecular Biology,1990,37(3):387-394.
[10]Bradbury M. J., Akana S. F., Cascio C. S., et al. Regulation of basal ACTH secretion by corticosterone is mediated by both type I (MR) and type Ⅱ (GR) receptors in rat brain[J]. The Journal of Steroid Biochemistry and Molecular Biology,1991,40(1-3):133-142.
[11]Pavlides C., Ogawa S., Kimura A., et al. Role of adrenal steroid mineralocorticoid and glucocorticoid receptors in long-term potentiation in the CA1 field of hippocampal slices[J]. Brain Res,1996,738(2):229-235.
[12]Herman J. P., Cullinan W. E. Neurocircuitry of stress:central control of the hypothalamo-pituitary-adrenocortical axis[J]. Trends Neurosci,1997,20(2):78-84.
[13]Kapoor Amita, Dunn Elizabeth, Kostaki Alice, et al. Fetal programming of hypothalamo-pituitary-adrenal function:prenatal stress and glucocorticoids[J]. The Journal of Physiology,2006,572(1):31-44.
[14]Weiler U., Claus R., Schnoebelen-Combes S., et al. Influence of age and genotype on endocrine parameters and growth performance:a comparative study in Wild boars, Meishan and Large White boars[J]. Livest Prod Sci,1998,54(1):21-31.
[15]Li L. A., Xia D., Wei S., et al. Characterization of adrenal ACTH signaling pathway and steroidogenic enzymes in Erhualian and Pietrain pigs with different plasma cortisol levels[J]. Steroids,2008,73(8):806-814.
[16]Li Liu An, Xia Dong, Bao En Dong, et al. Erhualian and Pietrain pigs exhibit distinct behavioral, endocrine and biochemical responses during transport[J]. Livest Sci,2008,113(2-3):169-177.
[17]Stocco D. M. StAR protein and the regulation of steroid hormone biosynthesis[J]. Annu Rev Physiol, 2001,63(1):193-213.
[18]Arukwe A. Steroidogenic acute regulatory (StAR) protein and cholesterol side-chain cleavage (P450scc)-regulated steroidogenesis as an organ-specific molecular and cellular target for endocrine disrupting chemicals in fish[J]. Cell Biol Toxicol,2008,24(6):527-540.
[19]Yamazaki Takeshi, Shimodaira Mika, Kuwahara Hifumi, et al. Tributyltin disturbs bovine adrenal steroidogenesis by two modes of action[J]. Steroids,2005,70(14):913-921.
[20]Wei Shi, Xia Dong, Li Liuan, et al. Breed-specific expression of hippocampal 11[beta]-hydroxysteroid dehydrogenases and glucocorticoid receptors in Erhualian and Pietrain pigs exhibiting distinct stress coping characteristics[J]. Livest Sci,2010,131(2-3):240-244.
[21]Llorente E., Brito M. L., Machado P., et al. Effect of prenatal stress on the hormonal response to acute and chronic stress and on immune parameters in the offspring[J]. J Physiol Biochem, 2002,58(3):143-149.
[22]Koehl M., Darnaudery M., Dulluc J., et al. Prenatal stress alters circadian activity of hypothalamo-pituitary-adrenal axis and hippocampal corticosteroid receptors in adult rats of both gender[J]. JNeurobiol,1999,40(3):302-315.
[23]Bertram C., Trowern A. R., Copin N., et al. The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase:potential molecular mechanisms underlying the programming of hypertension in utero[J]. Endocrinology, 2001,142(7):2841-2853.
[24]Nyirenda M. J., Lindsay R. S., Kenyon C. J., et al. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring[J]. J Clin Invest, 1998,101(10):2174-2181.
[25]Seckl Jonathan R. Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms[J]. Molecular and Cellular Endocrinology,2001,185(1-2):61-71.
[26]Otten Winfrried, Kanitz Ellen, Tuchscherer Margret, et al. Repeated administrations of adrenocorticotropic hormone during gestation in gilts:Effects on growth, behaviour and immune responses of their piglets[J]. Livest Sci,2007,106(2-3):261-270.
[27]Lillycrop K. A., Phillips E. S., Jackson A. A., et al. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring[J]. J Nutr,2005,135(6):1382-1386.
[28]Anacker Christoph, Zunszain Patricia A., Carvalho Livia A., et al. The glucocorticoid receptor:Pivot of depression and of antidepressant treatment?[J]. Psychoneuroendocrinology,2011,36(3):415-425.
[29]Labonte B., Yerko V., Gross J., et al. Differential glucocorticoid receptor exon 1(b), 1(c), and 1(h) expression and methylation in suicide completers with a history of childhood abuse[J]. Biol Psychiatry,2012,72(1):41-48.
[30]Beato M., Truss M., Chavez S. Control of transcription by steroid hormones[J]. Ann N Y Acad Sci, 1996,784(1):93-123.
[31]Kumar Raj, Thompson E. Brad. Gene regulation by the glucocorticoid receptor:Structure:function relationship[J]. The Journal of Steroid Biochemistry and Molecular Biology,2005,94(5):383-394.
[32]Almlof T., Wright A. P., Gustafsson J. A. Role of acidic and phosphorylated residues in gene activation by the glucocorticoid receptor[J]. J Biol Chem,1995,270(29):17535-17540.
[33]Encio I J, Detera-Wadleigh S D. The genomic structure of the human glucocorticoid receptor[J]. Journal of Biological Chemistry,1991,266(11):7182-7188.
[34]Sengupta S., Vonesch J. L., Waltzinger C., et al. Negative cross-talk between p53 and the glucocorticoid receptor and its role in neuroblastoma cells[J]. Embo Journal, 2000,19(22):6051-6064.
[35]Bruna A., Nicolas M., Munoz A., et al. Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by glucocorticoids[J]. EMBO J,2003,22(22):6035-6044.
[36]Kumar R., Thompson E. B. The structure of the nuclear hormone receptors[J]. Steroids, 1999,64(5):310-319.
[37]Pedersen K. B., Geng C. D., Vedeckis W. V. Three mechanisms are involved in glucocorticoid receptor autoregulation in a human T-lymphoblast cell line[J]. Biochemistry, 2004,43(34):10851-10858.
[38]Govindan M. V., Pothier F., Leclerc S., et al. Human glucocorticoid receptor gene promotor-homologous down regulation[J]. J Steroid Biochem,1991,40(1-3):317-323.
[39]Turner J. D., Schote A. B., Macedo J. A., et al. Tissue specific glucocorticoid receptor expression, a role for alternative first exon usage?[J]. Biochem Pharmacol,2006,72(11):1529-1537.
[40]Geng C. D., Vedeckis W. V. Steroid-responsive sequences in the human glucocorticoid receptor gene 1A promoter[J]. Mol Endocrinol,2004,18(4):912-924.
[41]Purton J. F., Monk J. A., Liddicoat D. R., et al. Expression of the glucocorticoid receptor from the 1A promoter correlates with T lymphocyte sensitivity to glucocorticoid-induced cell death[J]. JImmunol,2004,173(6):3816-3824.
[42]Nunez B. S., Vedeckis W. V. Characterization of promoter 1B in the human glucocorticoid receptor gene[J]. Mol Cell Endocrinol,2002,189(1-2):191-199.
[43]Russcher Henk, Dalm Virgil A., de Jong Frank H., et al. Associations between promoter usage and alternative splicing of the glucocorticoid receptor gene[J]. J Mol Endocrinol,2007,38(1-2):91-98.
[44]Yang J., DeFranco D. B. Assessment of glucocorticoid receptor-heat shock protein 90 interactions in vivo during nucleocytoplasmic trafficking[J]. Mol Endocrinol,1996,10(1):3-13.
[45]SMITH,#160, F. D., et al. Steroid receptors and their associated proteins [M]. Chevy Chase, MD, ETATS-UNIS:Endocrine Society,1993.
[46]Wang Jen-Chywan, Derynck Mika Kakefuda, Nonaka Daisuke F., et al. Chromatin immunoprecipitation (ChIP) scanning identifies primary glucocorticoid receptor target genes[J]. Proceedings of the National Academy of Sciences of the United States of America, 2004,101(44):15603-15608.
[47]Dostert A., Heinzel T. Negative glucocorticoid receptor response elements and their role in glucocorticoid action[J]. Curr Pharm Des,2004,10(23):2807-2816.
[48]Gametchu B, Watson C S, Wu S. Use of receptor antibodies to demonstrate membrane glucocorticoid receptor in cells from human leukemic patients[J]. FASEB J,1993,7(13):1283-1292.
[49]Gametchu Bahiru, Watson Cheryl S. Correlation of membrane glucocorticoid receptor levels with glucocorticoid-induced apoptotic competence using mutant leukemic and lymphoma cells lines[J]. Journal of Cellular Biochemistry,2002,87(2):133-146.
[50]Oakley R. H., Cidlowski J. A. Cellular processing of the glucocorticoid receptor gene and protein: new mechanisms for generating tissue-specific actions of glucocorticoids[J]. J Biol Chem, 2011,286(5):3177-3184.
[51]Lu N. Z., Cidlowski J. A. The origin and functions of multiple human glucocorticoid receptor isoforms[J]. Ann N Y Acad Sci,2004,1024(1):102-123.
[52]Kino T., Su Y. A., Chrousos G. P. Human glucocorticoid receptor isoform beta:recent understanding of its potential implications in physiology and pathophysiology[J]. Cell MolLife Sci, 2009,66(21):3435-3448.
[53]Pujols L., Mullol J., Roca-Ferrer J., et al. Expression of glucocorticoid receptor alpha-and beta-isoforms in human cells and tissues[J]. Am J Physiol Cell Physiol,2002,283(4):C1324-1331.
[54]Sousa Ana R., Lane Stephen J., Cidlowski John A., et al. Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor β-isoform[J]. Journal of Allergy and Clinical Immunology,2000,105(5):943-950.
[55]Honda Mitsunori, Orii Fumika, Ayabe Tokiyoshi, et al. Expression of glucocorticoid receptor β in lymphocytes of patients with glucocorticoid-resistant ulcerative colitis[J]. Gastroenterology, 2000,118(5):859-866.
[56]Yudt M. R., Cidlowski J. A. Molecular identification and characterization of a and b forms of the glucocorticoid receptor[J]. Mol Endocrinol,2001,15(7):1093-1103.
[57]DeRijk R. H., Schaaf M., de Kloet E. R. Glucocorticoid receptor variants:clinical implications[J]. J Steroid Biochem Mol Biol,2002,81(2):103-122.
[58]Stevens Adam, Donn Rachelle, Ray David. Regulation of glucocorticoid receptor gamma (GRy) by glucocorticoid receptor haplotype and glucocorticoid[J]. Clin Endocrinol,2004,61(3):327-331.
[59]Alt S. R., Turner J. D., Klok M. D., et al. Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed[J]. Psychoneuroendocrinology,2010,35(4):544-556.
[60]Berger Shelley L. Histone modifications in transcriptional regulation[J]. Curr Opin Genet Dev, 2002,12(2):142-148.
[61]Jones N. C., Rigby P. W., Ziff E. B. Trans-acting protein factors and the regulation of eukaryotic transcription:lessons from studies on DN A tumor viruses[J]. Genes Dev,1988,2(3):267-281.
[62]Illingworth Robert S., Bird Adrian P. CpG islands-'A rough guide'[J]. FEBS Lett, 2009,583(11):1713-1720.
[63]Creusot F., Acs G, Christman J. K. Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2'-deoxycytidine[J]. J Biol Chem, 1982,257(4):2041-2048.
[64]Antequera F, Bird A. Number of CpG islands and genes in human and mouse[J]. Proceedings of the National Academy of Sciences,1993,90(24):11995-11999.
[65]Kim M., Long T. I., Arakawa K., et al. DNA methylation as a biomarker for cardiovascular disease risk[J]. PLoS One,2010,5(3):e9692.
[66]Kohonen-Corish M. R., Sigglekow N. D., Susanto J., et al. Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer[J]. Oncogene, 2007,26(30):4435-4441.
[67]Robertson K. D., Wolffe A. P. DNA methylation in health and disease[J]. Nat Rev Genet, 2000,1(1):11-19.
[68]Dobosy J. R., Selker E. U. Emerging connections between DNA methylation and histone acetylation[J]. Cell Mol Life Sci,2001,58(5):721-727.
[69]Hermann R., Doerfler W. Interference with protein binding at AP2 sites by sequence-specific methylation in the late E2A promoter of adenovirus type 2 DNA[J]. FEBS Lett, 1991,281(1-2):191-195.
[70]Weaver I. C., Cervoni N., Champagne F. A., et al. Epigenetic programming by maternal behavior[J]. Nat Neurosci,2004,7(8):847-854.
[71]McGowan P. O., Sasaki A., D'Alessio A. C., et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse[J]. Nat Neurosci,2009,12(3):342-348.
[72]Filiberto A. C., Maccani M. A., Koestler D., et al. Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta[J]. Epigenetics,2011,6(5):566-572.
[73]Lillycrop K. A., Slater-Jefferies J. L., Hanson M. A., et al. Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications[J]. Br J Nutr,2007,97(6):1064-1073.
[74]Cao-Lei L., Leija S. C., Kumsta R., et al. Transcriptional control of the human glucocorticoid receptor:identification and analysis of alternative promoter regions[J]. Hum Genet, 2011,129(5):533-543.
[75]Clark Susan J., Harrison Janet, Molloy Peter L. Spl binding is inhibited by mCpmCpG methylation[J]. Gene,1997,195(1):67-71.
[76]McNeil C. J., Nwagwu M. O., Finch A. M., et al. Glucocorticoid exposure and tissue gene expression of llbeta HSD-1, llbeta HSD-2, and glucocorticoid receptor in a porcine model of differential fetal growth [J]. Reproduction,2007,133(3):653-661.
[77]Ayoubi TA, Van De Ven WJ. Regulation of gene expression by alternative promoters[J]. FASEB J, 1996,10(4):453-460.
[78]Hughes Thomas A. Regulation of gene expression by alternative untranslated regions[J]. Trends in Genetics,2006,22(3):119-122.
[79]Zhang Shelley X. L., Searcy Tina R., Wu Yiman, et al. Alternative promoter usage and alternative splicing contribute to mRNA heterogeneity of mouse monocarboxylate transporter 2[J]. Physiological Genomics,2007,32(1):95-104.
[80]Modrek B., Lee C. A genomic view of alternative splicing[J]. Nat Genet,2002,30(1):13-19.
[81]Ishii H., Kobayashi M., Sakuma Y. Alternative promoter usage and alternative splicing of the rat estrogen receptor alpha gene generate numerous mRNA variants with distinct 5'-ends[J]. J Steroid Biochem Mol Biol,2010,118(1-2):59-69.
[82]Turner J. D., Muller C. P. Structure of the glucocorticoid receptor (NR3C1) gene 5'untranslated region:identification, and tissue distribution of multiple new human exon 1[J]. J Mol Endocrinol, 2005,35(2):283-292.
[83]Philipsen S., Suske G A tale of three fingers:the family of mammalian Sp/XKLF transcription factors[J]. Nucleic Acids Res,1999,27(15):2991-3000.
[84]Kaczynski J., Cook T., Urrutia R. Spl- and Kruppel-like transcription factors[J]. Genome Biol, 2003,4(2):206.
[85]Song J., Ugai H., Kanazawa I., et al. Independent repression of a GC-rich housekeeping gene by Spl and MAZ involves the same cis-elements[J]. J Biol Chem,2001,276(23):19897-19904.
[86]Ye Xiaobing, Liu Shu Fang. Lipopolysaccharide Down-regulates Spl Binding Activity by Promoting Spl Protein Dephosphorylation and Degradation[J]. Journal of Biological Chemistry, 2002,277(35):31863-31870.
[87]Olofsson B. A., Kelly C. M., Kim J., et al. Phosphorylation of Spl in response to DNA damage by ataxia telangiectasia-mutated kinase[J]. Mol Cancer Res,2007,5(12):1319-1330.
[88]Zheng X. L., Matsubara S., Diao C., et al. Activation of apolipoprotein Al gene expression by protein kinase A and kinase C through transcription factor, Sp1[J]. J Biol Chem, 2000,275(41):31747-31754.
[89]Olofsson Beatrix A., Kelly Crystal M., Kim Jiyoon, et al. Phosphorylation of Sp1 in Response to DNA Damage by Ataxia Telangiectasia-Mutated Kinase[J]. Molecular Cancer Research, 2007,5(12):1319-1330.
[90]Song Chao-Zhong, Keller Kimberly, Murata Ken, et al. Functional Interaction between Coactivators CBP/p300, PCAF, and Transcription Factor FKLF2[J]. J Biol Chem,2002,277(9):7029-7036.
[91]Doetzlhofer A., Rotheneder H., Lagger G, et al. Histone deacetylase 1 can repress transcription by binding to Sp1[J]. Mol Cell Biol,1999,19(8):5504-5511.
[92]Li L., He S., Sun J. M., et al. Gene regulation by Spl and Sp3[J]. Biochem Cell Biol, 2004,82(4):460-471.
[93]Nobukuni Y., Smith C. L., Hager G L., et al. Characterization of the human glucocorticoid receptor promoter[J]. Biochemistry,1995,34(25):8207-8214.
[94]Suehiro T., Kaneda T., Ikeda Y., et al. Regulation of human glucocorticoid receptor gene transcription by Spl and p53[J]. Mol Cell Endocrinol,2004,222(1-2):33-40.
[95]Chrivia John C, Kwok Roland P. S., Lamb Ned, et al. Phosphorylated CREB binds specifically to the nuclear protein CBP[J]. Nature,1993,365(6449):855-859.
[96]Chen C. J., Deng Z., Kim A. Y., et al. Stimulation of CREB binding protein nucleosomal histone acetyltransferase activity by a class of transcriptional activators[J]. Mol Cell Biol, 2001,21(2):476-487.
[97]Sheng Morgan, McFadden Grant, Greenberg Michael E. Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB[J]. Neuron, 1990,4(4):571-582.
[98]Wadzinski B E, Wheat W H, Jaspers S, et al. Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation[J]. Molecular and Cellular Biology,1993,13(5):2822-2834.
[99]Govindan M. V. Recruitment of cAMP-response element-binding protein and histone deacetylase has opposite effects on glucocorticoid receptor gene transcription[J]. J Biol Chem, 2010,285(7):4489-4510.
[100]Erdeljan P., Andrews M. H., MacDonald J. F., et al. Glucocorticoids and serotonin alter glucocorticoid receptor mRNA levels in fetal guinea-pig hippocampal neurons, in vitro[J]. Reprod Fertil Dev,2005,17(7):743-749.
[101]Mitchell J. B., Rowe W., Boksa P., et al. Serotonin regulates type Ⅱ corticosteroid receptor binding in hippocampal cell cultures[J]. J Neurosci,1990,10(6):1745-1752.
[102]Penuelas I., Encio I. J., Lopez-Moratalla N., et al. cAMP activates transcription of the human glucocorticoid receptor gene promoter[J]. J Steroid Biochem,1998,67(2):89-94.
[103]Dong Y., Aronsson M., Gustafsson J. A., et al. The mechanism of cAMP-induced glucocorticoid receptor expression. Correlation to cellular glucocorticoid response[J], J Biol Chem, 1989,264(23):13679-13683.
[104]Kuwahara S., Arima H., Banno R., et al. Regulation of vasopressin gene expression by cAMP and glucocorticoids in parvocellular neurons of the paraventricular nucleus in rat hypothalamic organotypic cultures[J]. J Neurosci,2003,23(32):10231-10237.
[105]Skalweit A., Doller A., Huth A., et al. Posttranscriptional control of renin synthesis:identification of proteins interacting with renin mRNA 3'-untranslated region[J]. Circ Res,2003,92(4):419-427.
[106]Farmer G, Colgan J, Nakatani Y, et al. Functional interaction between p53, the TATA-binding protein (TBP), andTBP-associated factors in vivo[J]. Molecular and Cellular Biology, 1996,16(8):4295-4304.
[107]Walker Kristen K., Levine Arnold J. Identification of a novel p53 functional domain that is necessary for efficient growth suppression[J]. Proceedings of the National Academy of Sciences, 1996,93(26):15335-15340.
[108]Maddocks Oliver, Vousden Karen. Metabolic regulation by p53[J]. Journal of Molecular Medicine, 2011,89(3):237-245.
[109]Zhou M., Gu L., Li F., et al. DNA damage induces a novel p53-survivin signaling pathway regulating cell cycle and apoptosis in acute lymphoblastic leukemia cells[J]. J Pharmacol Exp Ther, 2002,303(1):124-131.
[110]Lagger G, Doetzlhofer A., Schuettengruber B., et al. The tumor suppressor p53 and histone deacetylase 1 are antagonistic regulators of the cyclin-dependent kinase inhibitor p21/WAFl/CIPl gene[J]. Mol Cell Biol,2003,23(8):2669-2679.
[111]Caelles C, Helmberg A., Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes[J]. Nature,1994,370(6486):220-223.
[112]Jacks T., Strasser A. Hot papers-Apoptosis-DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2 by A. Strasser, A.W. Harris, T. Jacks, S. Cory-Comments[J]. Scientist,1996,10(23):15-15.
[113]Nishimura K., Makino S., Tanaka Y, et al. Altered expression of p53 mRNA in the brain and pituitary during repeated immobilization stress:negative correlation with glucocorticoid receptor mRNA levels[J]. J Neuroendocrinol,2004,16(I):84-91.
[114]Sengupta S., Vonesch J. L., Waltzinger C, et al. Negative cross-talk between p53 and the glucocorticoid receptor and its role in neuroblastoma cellsfJ]. EMBO J,2000,19(22):6051-6064.
[115]Sengupta S., Wasylyk B. Physiological and pathological consequences of the interactions of the p53 tumor suppressor with the glucocorticoid, androgen, and estrogen receptors[J]. Ann N Y Acad Sci, 2004,1024(l):54-71.
[116]Crochemore C, Michaelidis T. M., Fischer D., et al. Enhancement of p53 activity and inhibition of neural cell proliferation by glucocorticoid receptor activation[J]. FASEB J,2002,16(8):761-770.
[117]Thiel G, Cibelli G Regulation of life and death by the zinc finger transcription factor Egr-1 [J]. J Cell Physiol,2002,193(3):287-292.
[118]Gashler A L, Swaminathan S, Sukhatme V P. A novel repression module, an extensive activation domain, and a bipartite nuclear localization signal defined in the immediate-early transcription factor Egr-1[J]. Molecular and Cellular Biology,1993,13(8):4556-4571.
[119]De Kloet E. Ronald, Rosenfeld Patricia, Van Eekelen J. Anke M., et al. Stress, glucocorticoids and development [M]. GJ. Boer M. G P. Feenstra M. Mirmiran D. F. Swaab, Haaren F. Van (eds). Progress in Brain Research. Elsevier,1988:101-120.
[120]Meaney Michael J., Szyf Moshe. Maternal care as a model for experience-dependent chromatin plasticity?[J]. Trends in Neurosciences,2005,28(9):456-463.
[121]Seto E., Shi Y., Shenk T. Yyl Is an Initiator Sequence-Binding Protein That Directs and Activates Transcription Invitro[J]. Nature,1991,354(6350):241-245.
[122]Affar El Bachir, Gay Frederique, Shi Yujiang, et al. Essential Dosage-Dependent Functions of the Transcription Factor Yin Yang 1 in Late Embryonic Development and Cell Cycle Progression[J]. Molecular and Cellular Biology,2006,26(9):3565-3581.
[123]Yao Ya-Li, Ghosh Subir, Fang Yong, et al. Cloning, chromosomal localization and promoter analysis of the human transcription factor YY1[J]. Nucleic Acids Research,1998,26(16):3776-3783.
[124]Heintz N., Sive H. L., Roeder R. G Regulation of human histone gene expression:kinetics of accumulation and changes in the rate of synthesis and in the half-lives of individual histone mRNAs during the HeLa cell cycle[J]. Mol Cell Biol,1983,3(4):539-550.
[125]Breslin M. B., Vedeckis W. V. The human glucocorticoid receptor promoter upstream sequences contain binding sites for the ubiquitous transcription factor, Yin Yang 1[J]. J Steroid Biochem, 1998,67(5-6):369-381.
[126]Nyirenda M. J., Lindsay R. S., Kenyon C. J., et al. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspringfj]. J Clin Invest, 1998,101(10):2174-2181.
[127]Fan Z., Du H., Zhang M., et al. Direct regulation of glucose and not insulin on hepatic hexose-6-phosphate dehydrogenase and 1 lbeta-hydroxysteroid dehydrogenase type 1[J]. Mol Cell Endocrinol,2011,333(1):62-69.
[128]Dostert A., Heinzel T. Negative glucocorticoid receptor response elements and their role in glucocorticoid action[J]. Current Pharmaceutical Design,2004,10(23):2807-2816.
[129]Heck S., Kullmann M., Gast A., et al. A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1[J]. EMBO J, 1994,13(17):4087-4095.
[130]Geng C. D., Vedeckis W. V. c-Myb and members of the c-Ets family of transcription factors act as molecular switches to mediate opposite steroid regulation of the human glucocorticoid receptor 1A promoter[J]. J Biol Chem,2005,280(52):43264-43271.
[131]Ramdas J., Liu W., Harmon J. M. Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells[J]. Cancer Res, 1999,59(6):1378-1385.
[132]Rosewicz S, McDonald A R, Maddux B A, et al. Mechanism of glucocorticoid receptor down-regulation by glucocorticoids[J]. Journal of Biological Chemistry,1988,263(6):2581-2584.
[133]Geng C. D., Schwartz J. R., Vedeckis W. V. A conserved molecular mechanism is responsible for the auto-up-regulation of glucocorticoid receptor gene promoters [J]. Mol Endocrinol, 2008,22(12):2624-2642.
[134]Kuo M. H., Allis C. D. Roles of histone acetyltransferases and deacetylases in gene regulation[J]. Bioessays,1998,20(8):615-626.
[135]Allfrey V. G., Faulkner R., Mirsky A. E. Acetylation and Methylation of Histones and Their Possible Role in the Regulation of Rna Synthesis[J]. Proc Natl Acad Sci U S A,1964,51(1):786-794.
[136]de Ruijter A. J., van Gennip A. H., Caron H. N., et al. Histone deacetylases (HDACs): characterization of the classical HDAC family[J]. Biochem J,2003,370(Pt 3):737-749.
[137]Taunton Jack, Hassig Christian A., Schreiber Stuart L. A Mammalian Histone Deacetylase Related to the Yeast Transcriptional Regulator Rpd3p[J]. Science,1996,272(5260):408-411.
[138]Chen F., Watson C. S., Gametchu B. Multiple glucocorticoid receptor transcripts in membrane glucocorticoid receptor-enriched S-49 mouse lymphoma cells[J]. J Cell Biochem, 1999,74(3):418-429.
[139]McCormick J. A., Lyons V., Jacobson M. D., et al.5'-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific:differential regulation of variant transcripts by early-life events[J]. Mol Endocrinol,2000,14(4):506-517.
[140]Boullion R. D., Mokelke E. A., Wamhoff B. R., et al. Porcine model of diabetic dyslipidemia:insulin and feed algorithms for mimicking diabetes mellitus in humans[J]. Comp Med,2003,53(1):42-52.
[141]Bockmuhl Y., Murgatroyd C. A., Kuczynska A., et al. Differential Regulation and Function of 5'-Untranslated GR-Exon 1 Transcripts[J]. Mol Endocrinol,2011.
[142]Presul Elisabeth, Schmidt Stefan, Kofler Reinhard, et al. Identification, tissue expression, and glucocorticoid responsiveness of alternative first exons of the human glucocorticoid receptor[J]. J Mol Endocrinol,2007,38(1-2):79-90.
[143]Livak K. J., Schmittgen T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method[J]. Methods,2001,25(4):402-408.
[144]Bellido M. L., Radpour R., Lapaire O., et al. MALDI-TOF mass array analysis of RASSF1A and SERPINB5 methylation patterns in human placenta and plasma[J]. Biol Reprod, 2010,82(4):745-750.
[145]Takai D., Jones P. A. The CpG island searcher:a new WWW resource[J]. In Silico Biol, 2003,3(3):235-240.
[146]Weber Michael, Hellmann Ines, Stadler Michael B., et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome[J]. Nat Genet, 2007,39(4):457-466.
[147]Yau J. L., Noble J., Chapman K. E., et al. Differential regulation of variant glucocorticoid receptor mRNAs in the rat hippocampus by the antidepressant fluoxetine[J]. Mol Brain Res, 2004,129(1-2):189-192.
[148]Lillycrop K. A., Phillips E. S., Torrens C., et al. Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring[J]. Br J Nutr,2008,100(2):278-282.
[149]Nijland Mark J., Mitsuya Kozoh, Li Cun, et al. Epigenetic modification of fetal baboon hepatic phosphoenolpyruvate carboxykinase following exposure to moderately reduced nutrient availability[J]. The Journal of Physiology,2010,588(8):1349-1359.
[150]Desautes C., Sarrieau A., Caritez J. C., et al. Behavior and pituitary-adrenal function in large white and Meishan pigs[J]. Domest Anim Endocrin,1999,16(4):193-205.
[151]Hug Martin, Silke John, Georgiev Oleg, et al. Transcriptional repression by methylation: cooperativity between a CpG cluster in the promoter and remote CpG-rich regions[J]. FEBS Lett, 1996,379(3):251-254.
[152]Kudo S. Methyl-CpG-binding protein MeCP2 represses Spl-activated transcription of the human leukosialin gene when the promoter is methylated[J]. Molecular and Cellular Biology, 1998,18(9):5492-5499.
[153]Lewis Joe, Bird Adrian. DNA methylation and chromatin structure[J]. FEBS Lett, 1991,285(2):155-159.
[154]Rudiger J. J., Roth M., Bihl M. P., et al. Interaction of C/EBPalpha and the glucocorticoid receptor in vivo and in nontransformed human cells[J]. FASEB J,2002,16(2):177-184.
[155]Baserga M., Kaur R., Hale M. A., et al. Fetal growth restriction alters transcription factor binding and epigenetic mechanisms of renal 11beta-hydroxysteroid dehydrogenase type 2 in a sex-specific manner[J]. Am J Physiol Regul Integr Comp Physiol,2010,299(1):R334-342.
[156]Rougeulle C., Navarro P., Avner P. Promoter-restricted H3 Lys 4 di-methylation is an epigenetic mark for monoallelic expression[J]. Hum Mol Genet,2003,12(24):3343-3348.
[157]Osterloh Lisa, von Eyss Bjorn, Schmit Fabienne, et al. The human synMuv-like protein LIN-9 is required for transcription of G2/M genes and for entry into mitosis[J]. EMBO J, 2007,26(1):144-157.
[158]Marelli S. P., Terova G., Cozzi M. C., et al. Gene expression of hepatic glucocorticoid receptor NR3C1 and correlation with plasmatic corticosterone in Italian chickens[J]. Anim Biotechnol, 2010,21(2):140-148.
[159]Li X., Yang X., Shan B., et al. Meat quality is associated with muscle metabolic status but not contractile myofiber type composition in premature pigs[J]. Meat Sci,2009,81(1):218-223.
[160]Mostyn A., Sebert S., Litten J. C., et al. Influence of porcine genotype on the abundance of thyroid hormones and leptin in sow milk and its impact on growth, metabolism and expression of key adipose tissue genes in offspring[J]. J Endocrinol,2006,190(3):631-639.
[161]Klemcke H. G, Sampath Kumar R., Yang K., et al. llbeta-hydroxysteroid dehydrogenase and glucocorticoid receptor messenger RNA expression in porcine placentae:effects of stage of gestation, breed, and uterine environment[J]. Biol Reprod,2003,69(6):1945-1950.
[162]Liu Yanjun, Nakagawa Yuichi, Wang Ying, et al. Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice[J]. J Mol Endocrinol,2008,41(2):53-64.
[163]van der Velden A. W., Thomas A. A. The role of the 5'untranslated region of an mRNA in translation regulation during development[J]. Int J Biochem Cell Biol,1999,31(1):87-106.
[164]Kreth S., Ledderose C., Kaufmann I., et al. Differential expression of 5'-UTR splice variants of the adenosine A2A receptor gene in human granulocytes:identification, characterization, and functional impact on activation[J]. FASEB J,2008,22(9):3276-3286.
[165]Dong Y., Aronsson M., Gustafsson J. A., et al. The mechanism of cAMP-induced glucocorticoid receptor expression. Correlation to cellular glucocorticoid response[J]. J Bio IChem, 1989,264(23):13679-13683.
[166]Shahbazian Mona D., Grunstein Michael. Functions of Site-Specific Histone Acetylation and Deacetylation[J]. Annu Rev Biochem,2007,76(1):75-100.
[167]Dalvai M., Mondesert O., Bourdon J. C., et al. Cdc25B is negatively regulated by p53 through Spl and NF-Y transcription factors[J]. Oncogene,2011,30(19):2282-2288.
[168]De Amicis F., Giordano F., Vivacqua A., et al. Resveratrol, through NF-Y/p53/Sin3/HDACl complex phosphorylation, inhibits estrogen receptor{alpha} gene expression via p38MAPK/CK2 signaling in human breast cancer cells[J]. FASEB J,2011,25(10):3695-3707.
[169]Xu H., Lu A., Sharp F. R. Regional genome transcriptional response of adult mouse brain to hypoxia[J]. BMC Genomics,2011,12(2):499-505.
[170]Baserga M., Hale M. A., McKnight R. A., et al. Uteroplacental insufficiency alters hepatic expression, phosphorylation, and activity of the glucocorticoid receptor in fetal IUGR rats[J]. Am J Physiol Regul Integr Comp Physiol,2005,289(5):R1348-1353.
[171]Rasti M., Arabsolghar R., Khatooni Z., et al. p53 Binds to estrogen receptor 1 promoter in human breast cancer cells[J]. Pathol Oncol Res,2012,18(2):169-175.
[172]Saffer J D, Jackson S P, Annarella M B. Developmental expression of Spl in the mouse[J]. Molecular and Cellular Biology,1991,11(4):2189-2199.
[173]Samson S. L., Wong N. C. Role of Sp1 in insulin regulation of gene expression[J]. J Mol Endocrinol, 2002,29(3):265-279.
[174]Macleod D., Charlton J., Mullins J., et al. Spl sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island[J]. Genes Dev,1994,8(19):2282-2292.
[175]Iwahori Satoko, Yasui Yoshihiro, Kudoh Ayumi, et al. Identification of phosphorylation sites on transcription factor Spl in response to DNA damage and its accumulation at damaged sitesfJ]. Cell Signal,2008,20(10):1795-1803.
[176]Olsson T., Mohammed A. K., Donaldson L. F., et al. Transcription factor AP-2 gene expression in adult rat hippocampal regions:effects of environmental manipulations[J]. Neurosci Lett, 1995,189(2):113-116.
[177]Kang H. T., Ju J. W., Cho J. W., et al. Down-regulation of Spl activity through modulation of O-glycosylation by treatment with a low glucose mimetic,2-deoxyglucose[J]. JBiolChem, 2003,278(51):51223-51231.
[178]Koutsodontis George, Tentes Ioannis, Papakosta Paraskevi, et al. Spl Plays a Critical Role in the Transcriptional Activation of the Human Cyclin-dependent Kinase Inhibitor p21 WAF1/Cipl Gene by the p53 Tumor Suppressor Protein[J]. Journal of Biological Chemistry, 2001,276(31):29116-29125.
[179]Thornborrow E. C., Manfredi J. J. The tumor suppressor protein p53 requires a cofactor to activate transcriptionally the human BAX promoter[J]. J Biol Chem,2001,276(19):15598-15608.
[180]Sangild P. T., Hilsted L., Nexo E., et al. Vaginal birth versus elective caesarean section:effects on gastric function in the neonate[J]. Exp Physiol,1995,80(1):147-157.
[181]Yamabe Yukako, Shimamoto Akira, Goto Makoto, et al. Spl-Mediated Transcription of the Werner Helicase Gene Is Modulated by Rb and p53[J]. Mol Cell Biol,1998,18(11):6191-6200.
[182]Angeloni S. V., Martin M. B., Garcia-Morales P., et al. Regulation of estrogen receptor-alpha expression by the tumor suppressor gene p53 in MCF-7 cells[J]. J Endocrinol,2004,180(3):497-504.
[183]Shirley S. H., Rundhaug J. E., Tian J., et al. Transcriptional regulation of estrogen receptor-alpha by p53 in human breast cancer cells[J]. Cancer Res,2009,69(8):3405-3414.
[2]Whitnall M. H. Regulation of the hypothalamic corticotropin-releasing hormone neurosecretory system[J]. Prog Neurobiol,1993,40(5):573-629.
[3]Herman J. P., Cullinan W. E., Watson S. J. Involvement of the bed nucleus of the stria terminalis in tonic regulation of paraventricular hypothalamic CRH and AVP mRNA expression[J]. J Neuroendocrinol,1994,6(4):433-442.
[4]Henry James. Biological basis of the stress response[J]. Integrative Physiological and Behavioral Science,1992,27(1):66-83.
[5]Kemeny Margaret E. The Psychobiology of Stress[J]. Current Directions in Psychological Science, 2003,12(4):124-129.
[6]Chrousos George P., Gold Philip W. A Healthy Body in a Healthy Mind—and Vice Versa—the Damaging Power of "Uncontrollable" Stress[J]. Journal of Clinical Endocrinology & Metabolism, 1998,83(6):1842-1845.
[7]Talge Nicole M., Neal Charles, Glover Vivette, et al. Antenatal maternal stress and long-term effects on child neurodevelopment:how and why?[J]. Journal of Child Psychology and Psychiatry, 2007,48(3-4):245-261.
[8]Jacobson L., Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis[J]. Endocr Rev,1991,12(2):118-134.
[9]de Kloet E. R., Reul J. M. H. M., Sutanto W. Corticosteroids and the brain[J]. The Journal of Steroid Biochemistry and Molecular Biology,1990,37(3):387-394.
[10]Bradbury M. J., Akana S. F., Cascio C. S., et al. Regulation of basal ACTH secretion by corticosterone is mediated by both type I (MR) and type Ⅱ (GR) receptors in rat brain[J]. The Journal of Steroid Biochemistry and Molecular Biology,1991,40(1-3):133-142.
[11]Pavlides C., Ogawa S., Kimura A., et al. Role of adrenal steroid mineralocorticoid and glucocorticoid receptors in long-term potentiation in the CA1 field of hippocampal slices[J]. Brain Res,1996,738(2):229-235.
[12]Herman J. P., Cullinan W. E. Neurocircuitry of stress:central control of the hypothalamo-pituitary-adrenocortical axis[J]. Trends Neurosci,1997,20(2):78-84.
[13]Kapoor Amita, Dunn Elizabeth, Kostaki Alice, et al. Fetal programming of hypothalamo-pituitary-adrenal function:prenatal stress and glucocorticoids[J]. The Journal of Physiology,2006,572(1):31-44.
[14]Weiler U., Claus R., Schnoebelen-Combes S., et al. Influence of age and genotype on endocrine parameters and growth performance:a comparative study in Wild boars, Meishan and Large White boars[J]. Livest Prod Sci,1998,54(1):21-31.
[15]Li L. A., Xia D., Wei S., et al. Characterization of adrenal ACTH signaling pathway and steroidogenic enzymes in Erhualian and Pietrain pigs with different plasma cortisol levels[J]. Steroids,2008,73(8):806-814.
[16]Li Liu An, Xia Dong, Bao En Dong, et al. Erhualian and Pietrain pigs exhibit distinct behavioral, endocrine and biochemical responses during transport[J]. Livest Sci,2008,113(2-3):169-177.
[17]Stocco D. M. StAR protein and the regulation of steroid hormone biosynthesis[J]. Annu Rev Physiol, 2001,63(1):193-213.
[18]Arukwe A. Steroidogenic acute regulatory (StAR) protein and cholesterol side-chain cleavage (P450scc)-regulated steroidogenesis as an organ-specific molecular and cellular target for endocrine disrupting chemicals in fish[J]. Cell Biol Toxicol,2008,24(6):527-540.
[19]Yamazaki Takeshi, Shimodaira Mika, Kuwahara Hifumi, et al. Tributyltin disturbs bovine adrenal steroidogenesis by two modes of action[J]. Steroids,2005,70(14):913-921.
[20]Wei Shi, Xia Dong, Li Liuan, et al. Breed-specific expression of hippocampal 11[beta]-hydroxysteroid dehydrogenases and glucocorticoid receptors in Erhualian and Pietrain pigs exhibiting distinct stress coping characteristics[J]. Livest Sci,2010,131(2-3):240-244.
[21]Llorente E., Brito M. L., Machado P., et al. Effect of prenatal stress on the hormonal response to acute and chronic stress and on immune parameters in the offspring[J]. J Physiol Biochem, 2002,58(3):143-149.
[22]Koehl M., Darnaudery M., Dulluc J., et al. Prenatal stress alters circadian activity of hypothalamo-pituitary-adrenal axis and hippocampal corticosteroid receptors in adult rats of both gender[J]. JNeurobiol,1999,40(3):302-315.
[23]Bertram C., Trowern A. R., Copin N., et al. The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase:potential molecular mechanisms underlying the programming of hypertension in utero[J]. Endocrinology, 2001,142(7):2841-2853.
[24]Nyirenda M. J., Lindsay R. S., Kenyon C. J., et al. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring[J]. J Clin Invest, 1998,101(10):2174-2181.
[25]Seckl Jonathan R. Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms[J]. Molecular and Cellular Endocrinology,2001,185(1-2):61-71.
[26]Otten Winfrried, Kanitz Ellen, Tuchscherer Margret, et al. Repeated administrations of adrenocorticotropic hormone during gestation in gilts:Effects on growth, behaviour and immune responses of their piglets[J]. Livest Sci,2007,106(2-3):261-270.
[27]Lillycrop K. A., Phillips E. S., Jackson A. A., et al. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring[J]. J Nutr,2005,135(6):1382-1386.
[28]Anacker Christoph, Zunszain Patricia A., Carvalho Livia A., et al. The glucocorticoid receptor:Pivot of depression and of antidepressant treatment?[J]. Psychoneuroendocrinology,2011,36(3):415-425.
[29]Labonte B., Yerko V., Gross J., et al. Differential glucocorticoid receptor exon 1(b), 1(c), and 1(h) expression and methylation in suicide completers with a history of childhood abuse[J]. Biol Psychiatry,2012,72(1):41-48.
[30]Beato M., Truss M., Chavez S. Control of transcription by steroid hormones[J]. Ann N Y Acad Sci, 1996,784(1):93-123.
[31]Kumar Raj, Thompson E. Brad. Gene regulation by the glucocorticoid receptor:Structure:function relationship[J]. The Journal of Steroid Biochemistry and Molecular Biology,2005,94(5):383-394.
[32]Almlof T., Wright A. P., Gustafsson J. A. Role of acidic and phosphorylated residues in gene activation by the glucocorticoid receptor[J]. J Biol Chem,1995,270(29):17535-17540.
[33]Encio I J, Detera-Wadleigh S D. The genomic structure of the human glucocorticoid receptor[J]. Journal of Biological Chemistry,1991,266(11):7182-7188.
[34]Sengupta S., Vonesch J. L., Waltzinger C., et al. Negative cross-talk between p53 and the glucocorticoid receptor and its role in neuroblastoma cells[J]. Embo Journal, 2000,19(22):6051-6064.
[35]Bruna A., Nicolas M., Munoz A., et al. Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by glucocorticoids[J]. EMBO J,2003,22(22):6035-6044.
[36]Kumar R., Thompson E. B. The structure of the nuclear hormone receptors[J]. Steroids, 1999,64(5):310-319.
[37]Pedersen K. B., Geng C. D., Vedeckis W. V. Three mechanisms are involved in glucocorticoid receptor autoregulation in a human T-lymphoblast cell line[J]. Biochemistry, 2004,43(34):10851-10858.
[38]Govindan M. V., Pothier F., Leclerc S., et al. Human glucocorticoid receptor gene promotor-homologous down regulation[J]. J Steroid Biochem,1991,40(1-3):317-323.
[39]Turner J. D., Schote A. B., Macedo J. A., et al. Tissue specific glucocorticoid receptor expression, a role for alternative first exon usage?[J]. Biochem Pharmacol,2006,72(11):1529-1537.
[40]Geng C. D., Vedeckis W. V. Steroid-responsive sequences in the human glucocorticoid receptor gene 1A promoter[J]. Mol Endocrinol,2004,18(4):912-924.
[41]Purton J. F., Monk J. A., Liddicoat D. R., et al. Expression of the glucocorticoid receptor from the 1A promoter correlates with T lymphocyte sensitivity to glucocorticoid-induced cell death[J]. JImmunol,2004,173(6):3816-3824.
[42]Nunez B. S., Vedeckis W. V. Characterization of promoter 1B in the human glucocorticoid receptor gene[J]. Mol Cell Endocrinol,2002,189(1-2):191-199.
[43]Russcher Henk, Dalm Virgil A., de Jong Frank H., et al. Associations between promoter usage and alternative splicing of the glucocorticoid receptor gene[J]. J Mol Endocrinol,2007,38(1-2):91-98.
[44]Yang J., DeFranco D. B. Assessment of glucocorticoid receptor-heat shock protein 90 interactions in vivo during nucleocytoplasmic trafficking[J]. Mol Endocrinol,1996,10(1):3-13.
[45]SMITH,#160, F. D., et al. Steroid receptors and their associated proteins [M]. Chevy Chase, MD, ETATS-UNIS:Endocrine Society,1993.
[46]Wang Jen-Chywan, Derynck Mika Kakefuda, Nonaka Daisuke F., et al. Chromatin immunoprecipitation (ChIP) scanning identifies primary glucocorticoid receptor target genes[J]. Proceedings of the National Academy of Sciences of the United States of America, 2004,101(44):15603-15608.
[47]Dostert A., Heinzel T. Negative glucocorticoid receptor response elements and their role in glucocorticoid action[J]. Curr Pharm Des,2004,10(23):2807-2816.
[48]Gametchu B, Watson C S, Wu S. Use of receptor antibodies to demonstrate membrane glucocorticoid receptor in cells from human leukemic patients[J]. FASEB J,1993,7(13):1283-1292.
[49]Gametchu Bahiru, Watson Cheryl S. Correlation of membrane glucocorticoid receptor levels with glucocorticoid-induced apoptotic competence using mutant leukemic and lymphoma cells lines[J]. Journal of Cellular Biochemistry,2002,87(2):133-146.
[50]Oakley R. H., Cidlowski J. A. Cellular processing of the glucocorticoid receptor gene and protein: new mechanisms for generating tissue-specific actions of glucocorticoids[J]. J Biol Chem, 2011,286(5):3177-3184.
[51]Lu N. Z., Cidlowski J. A. The origin and functions of multiple human glucocorticoid receptor isoforms[J]. Ann N Y Acad Sci,2004,1024(1):102-123.
[52]Kino T., Su Y. A., Chrousos G. P. Human glucocorticoid receptor isoform beta:recent understanding of its potential implications in physiology and pathophysiology[J]. Cell MolLife Sci, 2009,66(21):3435-3448.
[53]Pujols L., Mullol J., Roca-Ferrer J., et al. Expression of glucocorticoid receptor alpha-and beta-isoforms in human cells and tissues[J]. Am J Physiol Cell Physiol,2002,283(4):C1324-1331.
[54]Sousa Ana R., Lane Stephen J., Cidlowski John A., et al. Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor β-isoform[J]. Journal of Allergy and Clinical Immunology,2000,105(5):943-950.
[55]Honda Mitsunori, Orii Fumika, Ayabe Tokiyoshi, et al. Expression of glucocorticoid receptor β in lymphocytes of patients with glucocorticoid-resistant ulcerative colitis[J]. Gastroenterology, 2000,118(5):859-866.
[56]Yudt M. R., Cidlowski J. A. Molecular identification and characterization of a and b forms of the glucocorticoid receptor[J]. Mol Endocrinol,2001,15(7):1093-1103.
[57]DeRijk R. H., Schaaf M., de Kloet E. R. Glucocorticoid receptor variants:clinical implications[J]. J Steroid Biochem Mol Biol,2002,81(2):103-122.
[58]Stevens Adam, Donn Rachelle, Ray David. Regulation of glucocorticoid receptor gamma (GRy) by glucocorticoid receptor haplotype and glucocorticoid[J]. Clin Endocrinol,2004,61(3):327-331.
[59]Alt S. R., Turner J. D., Klok M. D., et al. Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed[J]. Psychoneuroendocrinology,2010,35(4):544-556.
[60]Berger Shelley L. Histone modifications in transcriptional regulation[J]. Curr Opin Genet Dev, 2002,12(2):142-148.
[61]Jones N. C., Rigby P. W., Ziff E. B. Trans-acting protein factors and the regulation of eukaryotic transcription:lessons from studies on DN A tumor viruses[J]. Genes Dev,1988,2(3):267-281.
[62]Illingworth Robert S., Bird Adrian P. CpG islands-'A rough guide'[J]. FEBS Lett, 2009,583(11):1713-1720.
[63]Creusot F., Acs G, Christman J. K. Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2'-deoxycytidine[J]. J Biol Chem, 1982,257(4):2041-2048.
[64]Antequera F, Bird A. Number of CpG islands and genes in human and mouse[J]. Proceedings of the National Academy of Sciences,1993,90(24):11995-11999.
[65]Kim M., Long T. I., Arakawa K., et al. DNA methylation as a biomarker for cardiovascular disease risk[J]. PLoS One,2010,5(3):e9692.
[66]Kohonen-Corish M. R., Sigglekow N. D., Susanto J., et al. Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer[J]. Oncogene, 2007,26(30):4435-4441.
[67]Robertson K. D., Wolffe A. P. DNA methylation in health and disease[J]. Nat Rev Genet, 2000,1(1):11-19.
[68]Dobosy J. R., Selker E. U. Emerging connections between DNA methylation and histone acetylation[J]. Cell Mol Life Sci,2001,58(5):721-727.
[69]Hermann R., Doerfler W. Interference with protein binding at AP2 sites by sequence-specific methylation in the late E2A promoter of adenovirus type 2 DNA[J]. FEBS Lett, 1991,281(1-2):191-195.
[70]Weaver I. C., Cervoni N., Champagne F. A., et al. Epigenetic programming by maternal behavior[J]. Nat Neurosci,2004,7(8):847-854.
[71]McGowan P. O., Sasaki A., D'Alessio A. C., et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse[J]. Nat Neurosci,2009,12(3):342-348.
[72]Filiberto A. C., Maccani M. A., Koestler D., et al. Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta[J]. Epigenetics,2011,6(5):566-572.
[73]Lillycrop K. A., Slater-Jefferies J. L., Hanson M. A., et al. Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications[J]. Br J Nutr,2007,97(6):1064-1073.
[74]Cao-Lei L., Leija S. C., Kumsta R., et al. Transcriptional control of the human glucocorticoid receptor:identification and analysis of alternative promoter regions[J]. Hum Genet, 2011,129(5):533-543.
[75]Clark Susan J., Harrison Janet, Molloy Peter L. Spl binding is inhibited by mCpmCpG methylation[J]. Gene,1997,195(1):67-71.
[76]McNeil C. J., Nwagwu M. O., Finch A. M., et al. Glucocorticoid exposure and tissue gene expression of llbeta HSD-1, llbeta HSD-2, and glucocorticoid receptor in a porcine model of differential fetal growth [J]. Reproduction,2007,133(3):653-661.
[77]Ayoubi TA, Van De Ven WJ. Regulation of gene expression by alternative promoters[J]. FASEB J, 1996,10(4):453-460.
[78]Hughes Thomas A. Regulation of gene expression by alternative untranslated regions[J]. Trends in Genetics,2006,22(3):119-122.
[79]Zhang Shelley X. L., Searcy Tina R., Wu Yiman, et al. Alternative promoter usage and alternative splicing contribute to mRNA heterogeneity of mouse monocarboxylate transporter 2[J]. Physiological Genomics,2007,32(1):95-104.
[80]Modrek B., Lee C. A genomic view of alternative splicing[J]. Nat Genet,2002,30(1):13-19.
[81]Ishii H., Kobayashi M., Sakuma Y. Alternative promoter usage and alternative splicing of the rat estrogen receptor alpha gene generate numerous mRNA variants with distinct 5'-ends[J]. J Steroid Biochem Mol Biol,2010,118(1-2):59-69.
[82]Turner J. D., Muller C. P. Structure of the glucocorticoid receptor (NR3C1) gene 5'untranslated region:identification, and tissue distribution of multiple new human exon 1[J]. J Mol Endocrinol, 2005,35(2):283-292.
[83]Philipsen S., Suske G A tale of three fingers:the family of mammalian Sp/XKLF transcription factors[J]. Nucleic Acids Res,1999,27(15):2991-3000.
[84]Kaczynski J., Cook T., Urrutia R. Spl- and Kruppel-like transcription factors[J]. Genome Biol, 2003,4(2):206.
[85]Song J., Ugai H., Kanazawa I., et al. Independent repression of a GC-rich housekeeping gene by Spl and MAZ involves the same cis-elements[J]. J Biol Chem,2001,276(23):19897-19904.
[86]Ye Xiaobing, Liu Shu Fang. Lipopolysaccharide Down-regulates Spl Binding Activity by Promoting Spl Protein Dephosphorylation and Degradation[J]. Journal of Biological Chemistry, 2002,277(35):31863-31870.
[87]Olofsson B. A., Kelly C. M., Kim J., et al. Phosphorylation of Spl in response to DNA damage by ataxia telangiectasia-mutated kinase[J]. Mol Cancer Res,2007,5(12):1319-1330.
[88]Zheng X. L., Matsubara S., Diao C., et al. Activation of apolipoprotein Al gene expression by protein kinase A and kinase C through transcription factor, Sp1[J]. J Biol Chem, 2000,275(41):31747-31754.
[89]Olofsson Beatrix A., Kelly Crystal M., Kim Jiyoon, et al. Phosphorylation of Sp1 in Response to DNA Damage by Ataxia Telangiectasia-Mutated Kinase[J]. Molecular Cancer Research, 2007,5(12):1319-1330.
[90]Song Chao-Zhong, Keller Kimberly, Murata Ken, et al. Functional Interaction between Coactivators CBP/p300, PCAF, and Transcription Factor FKLF2[J]. J Biol Chem,2002,277(9):7029-7036.
[91]Doetzlhofer A., Rotheneder H., Lagger G, et al. Histone deacetylase 1 can repress transcription by binding to Sp1[J]. Mol Cell Biol,1999,19(8):5504-5511.
[92]Li L., He S., Sun J. M., et al. Gene regulation by Spl and Sp3[J]. Biochem Cell Biol, 2004,82(4):460-471.
[93]Nobukuni Y., Smith C. L., Hager G L., et al. Characterization of the human glucocorticoid receptor promoter[J]. Biochemistry,1995,34(25):8207-8214.
[94]Suehiro T., Kaneda T., Ikeda Y., et al. Regulation of human glucocorticoid receptor gene transcription by Spl and p53[J]. Mol Cell Endocrinol,2004,222(1-2):33-40.
[95]Chrivia John C, Kwok Roland P. S., Lamb Ned, et al. Phosphorylated CREB binds specifically to the nuclear protein CBP[J]. Nature,1993,365(6449):855-859.
[96]Chen C. J., Deng Z., Kim A. Y., et al. Stimulation of CREB binding protein nucleosomal histone acetyltransferase activity by a class of transcriptional activators[J]. Mol Cell Biol, 2001,21(2):476-487.
[97]Sheng Morgan, McFadden Grant, Greenberg Michael E. Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB[J]. Neuron, 1990,4(4):571-582.
[98]Wadzinski B E, Wheat W H, Jaspers S, et al. Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation[J]. Molecular and Cellular Biology,1993,13(5):2822-2834.
[99]Govindan M. V. Recruitment of cAMP-response element-binding protein and histone deacetylase has opposite effects on glucocorticoid receptor gene transcription[J]. J Biol Chem, 2010,285(7):4489-4510.
[100]Erdeljan P., Andrews M. H., MacDonald J. F., et al. Glucocorticoids and serotonin alter glucocorticoid receptor mRNA levels in fetal guinea-pig hippocampal neurons, in vitro[J]. Reprod Fertil Dev,2005,17(7):743-749.
[101]Mitchell J. B., Rowe W., Boksa P., et al. Serotonin regulates type Ⅱ corticosteroid receptor binding in hippocampal cell cultures[J]. J Neurosci,1990,10(6):1745-1752.
[102]Penuelas I., Encio I. J., Lopez-Moratalla N., et al. cAMP activates transcription of the human glucocorticoid receptor gene promoter[J]. J Steroid Biochem,1998,67(2):89-94.
[103]Dong Y., Aronsson M., Gustafsson J. A., et al. The mechanism of cAMP-induced glucocorticoid receptor expression. Correlation to cellular glucocorticoid response[J], J Biol Chem, 1989,264(23):13679-13683.
[104]Kuwahara S., Arima H., Banno R., et al. Regulation of vasopressin gene expression by cAMP and glucocorticoids in parvocellular neurons of the paraventricular nucleus in rat hypothalamic organotypic cultures[J]. J Neurosci,2003,23(32):10231-10237.
[105]Skalweit A., Doller A., Huth A., et al. Posttranscriptional control of renin synthesis:identification of proteins interacting with renin mRNA 3'-untranslated region[J]. Circ Res,2003,92(4):419-427.
[106]Farmer G, Colgan J, Nakatani Y, et al. Functional interaction between p53, the TATA-binding protein (TBP), andTBP-associated factors in vivo[J]. Molecular and Cellular Biology, 1996,16(8):4295-4304.
[107]Walker Kristen K., Levine Arnold J. Identification of a novel p53 functional domain that is necessary for efficient growth suppression[J]. Proceedings of the National Academy of Sciences, 1996,93(26):15335-15340.
[108]Maddocks Oliver, Vousden Karen. Metabolic regulation by p53[J]. Journal of Molecular Medicine, 2011,89(3):237-245.
[109]Zhou M., Gu L., Li F., et al. DNA damage induces a novel p53-survivin signaling pathway regulating cell cycle and apoptosis in acute lymphoblastic leukemia cells[J]. J Pharmacol Exp Ther, 2002,303(1):124-131.
[110]Lagger G, Doetzlhofer A., Schuettengruber B., et al. The tumor suppressor p53 and histone deacetylase 1 are antagonistic regulators of the cyclin-dependent kinase inhibitor p21/WAFl/CIPl gene[J]. Mol Cell Biol,2003,23(8):2669-2679.
[111]Caelles C, Helmberg A., Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes[J]. Nature,1994,370(6486):220-223.
[112]Jacks T., Strasser A. Hot papers-Apoptosis-DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2 by A. Strasser, A.W. Harris, T. Jacks, S. Cory-Comments[J]. Scientist,1996,10(23):15-15.
[113]Nishimura K., Makino S., Tanaka Y, et al. Altered expression of p53 mRNA in the brain and pituitary during repeated immobilization stress:negative correlation with glucocorticoid receptor mRNA levels[J]. J Neuroendocrinol,2004,16(I):84-91.
[114]Sengupta S., Vonesch J. L., Waltzinger C, et al. Negative cross-talk between p53 and the glucocorticoid receptor and its role in neuroblastoma cellsfJ]. EMBO J,2000,19(22):6051-6064.
[115]Sengupta S., Wasylyk B. Physiological and pathological consequences of the interactions of the p53 tumor suppressor with the glucocorticoid, androgen, and estrogen receptors[J]. Ann N Y Acad Sci, 2004,1024(l):54-71.
[116]Crochemore C, Michaelidis T. M., Fischer D., et al. Enhancement of p53 activity and inhibition of neural cell proliferation by glucocorticoid receptor activation[J]. FASEB J,2002,16(8):761-770.
[117]Thiel G, Cibelli G Regulation of life and death by the zinc finger transcription factor Egr-1 [J]. J Cell Physiol,2002,193(3):287-292.
[118]Gashler A L, Swaminathan S, Sukhatme V P. A novel repression module, an extensive activation domain, and a bipartite nuclear localization signal defined in the immediate-early transcription factor Egr-1[J]. Molecular and Cellular Biology,1993,13(8):4556-4571.
[119]De Kloet E. Ronald, Rosenfeld Patricia, Van Eekelen J. Anke M., et al. Stress, glucocorticoids and development [M]. GJ. Boer M. G P. Feenstra M. Mirmiran D. F. Swaab, Haaren F. Van (eds). Progress in Brain Research. Elsevier,1988:101-120.
[120]Meaney Michael J., Szyf Moshe. Maternal care as a model for experience-dependent chromatin plasticity?[J]. Trends in Neurosciences,2005,28(9):456-463.
[121]Seto E., Shi Y., Shenk T. Yyl Is an Initiator Sequence-Binding Protein That Directs and Activates Transcription Invitro[J]. Nature,1991,354(6350):241-245.
[122]Affar El Bachir, Gay Frederique, Shi Yujiang, et al. Essential Dosage-Dependent Functions of the Transcription Factor Yin Yang 1 in Late Embryonic Development and Cell Cycle Progression[J]. Molecular and Cellular Biology,2006,26(9):3565-3581.
[123]Yao Ya-Li, Ghosh Subir, Fang Yong, et al. Cloning, chromosomal localization and promoter analysis of the human transcription factor YY1[J]. Nucleic Acids Research,1998,26(16):3776-3783.
[124]Heintz N., Sive H. L., Roeder R. G Regulation of human histone gene expression:kinetics of accumulation and changes in the rate of synthesis and in the half-lives of individual histone mRNAs during the HeLa cell cycle[J]. Mol Cell Biol,1983,3(4):539-550.
[125]Breslin M. B., Vedeckis W. V. The human glucocorticoid receptor promoter upstream sequences contain binding sites for the ubiquitous transcription factor, Yin Yang 1[J]. J Steroid Biochem, 1998,67(5-6):369-381.
[126]Nyirenda M. J., Lindsay R. S., Kenyon C. J., et al. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspringfj]. J Clin Invest, 1998,101(10):2174-2181.
[127]Fan Z., Du H., Zhang M., et al. Direct regulation of glucose and not insulin on hepatic hexose-6-phosphate dehydrogenase and 1 lbeta-hydroxysteroid dehydrogenase type 1[J]. Mol Cell Endocrinol,2011,333(1):62-69.
[128]Dostert A., Heinzel T. Negative glucocorticoid receptor response elements and their role in glucocorticoid action[J]. Current Pharmaceutical Design,2004,10(23):2807-2816.
[129]Heck S., Kullmann M., Gast A., et al. A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1[J]. EMBO J, 1994,13(17):4087-4095.
[130]Geng C. D., Vedeckis W. V. c-Myb and members of the c-Ets family of transcription factors act as molecular switches to mediate opposite steroid regulation of the human glucocorticoid receptor 1A promoter[J]. J Biol Chem,2005,280(52):43264-43271.
[131]Ramdas J., Liu W., Harmon J. M. Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells[J]. Cancer Res, 1999,59(6):1378-1385.
[132]Rosewicz S, McDonald A R, Maddux B A, et al. Mechanism of glucocorticoid receptor down-regulation by glucocorticoids[J]. Journal of Biological Chemistry,1988,263(6):2581-2584.
[133]Geng C. D., Schwartz J. R., Vedeckis W. V. A conserved molecular mechanism is responsible for the auto-up-regulation of glucocorticoid receptor gene promoters [J]. Mol Endocrinol, 2008,22(12):2624-2642.
[134]Kuo M. H., Allis C. D. Roles of histone acetyltransferases and deacetylases in gene regulation[J]. Bioessays,1998,20(8):615-626.
[135]Allfrey V. G., Faulkner R., Mirsky A. E. Acetylation and Methylation of Histones and Their Possible Role in the Regulation of Rna Synthesis[J]. Proc Natl Acad Sci U S A,1964,51(1):786-794.
[136]de Ruijter A. J., van Gennip A. H., Caron H. N., et al. Histone deacetylases (HDACs): characterization of the classical HDAC family[J]. Biochem J,2003,370(Pt 3):737-749.
[137]Taunton Jack, Hassig Christian A., Schreiber Stuart L. A Mammalian Histone Deacetylase Related to the Yeast Transcriptional Regulator Rpd3p[J]. Science,1996,272(5260):408-411.
[138]Chen F., Watson C. S., Gametchu B. Multiple glucocorticoid receptor transcripts in membrane glucocorticoid receptor-enriched S-49 mouse lymphoma cells[J]. J Cell Biochem, 1999,74(3):418-429.
[139]McCormick J. A., Lyons V., Jacobson M. D., et al.5'-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific:differential regulation of variant transcripts by early-life events[J]. Mol Endocrinol,2000,14(4):506-517.
[140]Boullion R. D., Mokelke E. A., Wamhoff B. R., et al. Porcine model of diabetic dyslipidemia:insulin and feed algorithms for mimicking diabetes mellitus in humans[J]. Comp Med,2003,53(1):42-52.
[141]Bockmuhl Y., Murgatroyd C. A., Kuczynska A., et al. Differential Regulation and Function of 5'-Untranslated GR-Exon 1 Transcripts[J]. Mol Endocrinol,2011.
[142]Presul Elisabeth, Schmidt Stefan, Kofler Reinhard, et al. Identification, tissue expression, and glucocorticoid responsiveness of alternative first exons of the human glucocorticoid receptor[J]. J Mol Endocrinol,2007,38(1-2):79-90.
[143]Livak K. J., Schmittgen T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method[J]. Methods,2001,25(4):402-408.
[144]Bellido M. L., Radpour R., Lapaire O., et al. MALDI-TOF mass array analysis of RASSF1A and SERPINB5 methylation patterns in human placenta and plasma[J]. Biol Reprod, 2010,82(4):745-750.
[145]Takai D., Jones P. A. The CpG island searcher:a new WWW resource[J]. In Silico Biol, 2003,3(3):235-240.
[146]Weber Michael, Hellmann Ines, Stadler Michael B., et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome[J]. Nat Genet, 2007,39(4):457-466.
[147]Yau J. L., Noble J., Chapman K. E., et al. Differential regulation of variant glucocorticoid receptor mRNAs in the rat hippocampus by the antidepressant fluoxetine[J]. Mol Brain Res, 2004,129(1-2):189-192.
[148]Lillycrop K. A., Phillips E. S., Torrens C., et al. Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring[J]. Br J Nutr,2008,100(2):278-282.
[149]Nijland Mark J., Mitsuya Kozoh, Li Cun, et al. Epigenetic modification of fetal baboon hepatic phosphoenolpyruvate carboxykinase following exposure to moderately reduced nutrient availability[J]. The Journal of Physiology,2010,588(8):1349-1359.
[150]Desautes C., Sarrieau A., Caritez J. C., et al. Behavior and pituitary-adrenal function in large white and Meishan pigs[J]. Domest Anim Endocrin,1999,16(4):193-205.
[151]Hug Martin, Silke John, Georgiev Oleg, et al. Transcriptional repression by methylation: cooperativity between a CpG cluster in the promoter and remote CpG-rich regions[J]. FEBS Lett, 1996,379(3):251-254.
[152]Kudo S. Methyl-CpG-binding protein MeCP2 represses Spl-activated transcription of the human leukosialin gene when the promoter is methylated[J]. Molecular and Cellular Biology, 1998,18(9):5492-5499.
[153]Lewis Joe, Bird Adrian. DNA methylation and chromatin structure[J]. FEBS Lett, 1991,285(2):155-159.
[154]Rudiger J. J., Roth M., Bihl M. P., et al. Interaction of C/EBPalpha and the glucocorticoid receptor in vivo and in nontransformed human cells[J]. FASEB J,2002,16(2):177-184.
[155]Baserga M., Kaur R., Hale M. A., et al. Fetal growth restriction alters transcription factor binding and epigenetic mechanisms of renal 11beta-hydroxysteroid dehydrogenase type 2 in a sex-specific manner[J]. Am J Physiol Regul Integr Comp Physiol,2010,299(1):R334-342.
[156]Rougeulle C., Navarro P., Avner P. Promoter-restricted H3 Lys 4 di-methylation is an epigenetic mark for monoallelic expression[J]. Hum Mol Genet,2003,12(24):3343-3348.
[157]Osterloh Lisa, von Eyss Bjorn, Schmit Fabienne, et al. The human synMuv-like protein LIN-9 is required for transcription of G2/M genes and for entry into mitosis[J]. EMBO J, 2007,26(1):144-157.
[158]Marelli S. P., Terova G., Cozzi M. C., et al. Gene expression of hepatic glucocorticoid receptor NR3C1 and correlation with plasmatic corticosterone in Italian chickens[J]. Anim Biotechnol, 2010,21(2):140-148.
[159]Li X., Yang X., Shan B., et al. Meat quality is associated with muscle metabolic status but not contractile myofiber type composition in premature pigs[J]. Meat Sci,2009,81(1):218-223.
[160]Mostyn A., Sebert S., Litten J. C., et al. Influence of porcine genotype on the abundance of thyroid hormones and leptin in sow milk and its impact on growth, metabolism and expression of key adipose tissue genes in offspring[J]. J Endocrinol,2006,190(3):631-639.
[161]Klemcke H. G, Sampath Kumar R., Yang K., et al. llbeta-hydroxysteroid dehydrogenase and glucocorticoid receptor messenger RNA expression in porcine placentae:effects of stage of gestation, breed, and uterine environment[J]. Biol Reprod,2003,69(6):1945-1950.
[162]Liu Yanjun, Nakagawa Yuichi, Wang Ying, et al. Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice[J]. J Mol Endocrinol,2008,41(2):53-64.
[163]van der Velden A. W., Thomas A. A. The role of the 5'untranslated region of an mRNA in translation regulation during development[J]. Int J Biochem Cell Biol,1999,31(1):87-106.
[164]Kreth S., Ledderose C., Kaufmann I., et al. Differential expression of 5'-UTR splice variants of the adenosine A2A receptor gene in human granulocytes:identification, characterization, and functional impact on activation[J]. FASEB J,2008,22(9):3276-3286.
[165]Dong Y., Aronsson M., Gustafsson J. A., et al. The mechanism of cAMP-induced glucocorticoid receptor expression. Correlation to cellular glucocorticoid response[J]. J Bio IChem, 1989,264(23):13679-13683.
[166]Shahbazian Mona D., Grunstein Michael. Functions of Site-Specific Histone Acetylation and Deacetylation[J]. Annu Rev Biochem,2007,76(1):75-100.
[167]Dalvai M., Mondesert O., Bourdon J. C., et al. Cdc25B is negatively regulated by p53 through Spl and NF-Y transcription factors[J]. Oncogene,2011,30(19):2282-2288.
[168]De Amicis F., Giordano F., Vivacqua A., et al. Resveratrol, through NF-Y/p53/Sin3/HDACl complex phosphorylation, inhibits estrogen receptor{alpha} gene expression via p38MAPK/CK2 signaling in human breast cancer cells[J]. FASEB J,2011,25(10):3695-3707.
[169]Xu H., Lu A., Sharp F. R. Regional genome transcriptional response of adult mouse brain to hypoxia[J]. BMC Genomics,2011,12(2):499-505.
[170]Baserga M., Hale M. A., McKnight R. A., et al. Uteroplacental insufficiency alters hepatic expression, phosphorylation, and activity of the glucocorticoid receptor in fetal IUGR rats[J]. Am J Physiol Regul Integr Comp Physiol,2005,289(5):R1348-1353.
[171]Rasti M., Arabsolghar R., Khatooni Z., et al. p53 Binds to estrogen receptor 1 promoter in human breast cancer cells[J]. Pathol Oncol Res,2012,18(2):169-175.
[172]Saffer J D, Jackson S P, Annarella M B. Developmental expression of Spl in the mouse[J]. Molecular and Cellular Biology,1991,11(4):2189-2199.
[173]Samson S. L., Wong N. C. Role of Sp1 in insulin regulation of gene expression[J]. J Mol Endocrinol, 2002,29(3):265-279.
[174]Macleod D., Charlton J., Mullins J., et al. Spl sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island[J]. Genes Dev,1994,8(19):2282-2292.
[175]Iwahori Satoko, Yasui Yoshihiro, Kudoh Ayumi, et al. Identification of phosphorylation sites on transcription factor Spl in response to DNA damage and its accumulation at damaged sitesfJ]. Cell Signal,2008,20(10):1795-1803.
[176]Olsson T., Mohammed A. K., Donaldson L. F., et al. Transcription factor AP-2 gene expression in adult rat hippocampal regions:effects of environmental manipulations[J]. Neurosci Lett, 1995,189(2):113-116.
[177]Kang H. T., Ju J. W., Cho J. W., et al. Down-regulation of Spl activity through modulation of O-glycosylation by treatment with a low glucose mimetic,2-deoxyglucose[J]. JBiolChem, 2003,278(51):51223-51231.
[178]Koutsodontis George, Tentes Ioannis, Papakosta Paraskevi, et al. Spl Plays a Critical Role in the Transcriptional Activation of the Human Cyclin-dependent Kinase Inhibitor p21 WAF1/Cipl Gene by the p53 Tumor Suppressor Protein[J]. Journal of Biological Chemistry, 2001,276(31):29116-29125.
[179]Thornborrow E. C., Manfredi J. J. The tumor suppressor protein p53 requires a cofactor to activate transcriptionally the human BAX promoter[J]. J Biol Chem,2001,276(19):15598-15608.
[180]Sangild P. T., Hilsted L., Nexo E., et al. Vaginal birth versus elective caesarean section:effects on gastric function in the neonate[J]. Exp Physiol,1995,80(1):147-157.
[181]Yamabe Yukako, Shimamoto Akira, Goto Makoto, et al. Spl-Mediated Transcription of the Werner Helicase Gene Is Modulated by Rb and p53[J]. Mol Cell Biol,1998,18(11):6191-6200.
[182]Angeloni S. V., Martin M. B., Garcia-Morales P., et al. Regulation of estrogen receptor-alpha expression by the tumor suppressor gene p53 in MCF-7 cells[J]. J Endocrinol,2004,180(3):497-504.
[183]Shirley S. H., Rundhaug J. E., Tian J., et al. Transcriptional regulation of estrogen receptor-alpha by p53 in human breast cancer cells[J]. Cancer Res,2009,69(8):3405-3414.