Wnt信号通路及TCF7L2在2型糖尿病中的作用研究
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摘要
目的：研究2型糖尿病(T2DM)病人胰腺组织基因表达谱变化；筛选出Wnt信号通路相关的差异表达基因；并验证转录因子7类似物2(TCF7L2)依赖的Wnt信号通路相关基因的表达水平。
方法：胰腺组织标本来源于复旦大学上海医学院病理科组织样本库。芯片样本为2例T2DM(平均年龄55岁)和1例非糖尿病(50岁),PCR样本包括4例T2DM(72±3.72岁)和5例非糖尿病(52±11.1岁)。捐赠者死亡后迅速获取胰腺组织,抽提总RNA。应用18,000个克隆的杂交膜进行cDNA微阵列杂交。芯片数据标准化处理后,采用倍数法筛选糖尿病和非糖尿病之间的差异表达基因,阈值为1.5倍。采用DAVID (http://david. abcc. ncifcrf. gov/)在线分析工具,对差异表达基因进行日本京都基因和基因组百科全书代谢通路(KEGG pathway)功能富集分析。并用实时荧光定量PCR验证部分Wnt信号通路的基因表达,同时使用Western Blot检测核蛋白TCF7L2的水平。采用非参数Mann-Whiteney统计方法检验基因芯片结果与PCR结果的差异。
结果：基因芯片数据分析结果显示T2DM病人的胰腺差异表达基因有4200条；这些差异表达基因富集于Wnt信号通路、粘着斑、胰岛素信号通路、泛素化介导的蛋白降解通路,以及氧化磷酸化等40余条代谢通路；在Wnt信号通路中有41个差异表达基因,这些基因分布在Wnt信号通路的各个分支；定量PCR结果显示：与非糖尿病相比,T2DM胰腺Wnt4的mRNA相对表达量为1.691,Frizzled-4受体(FZD4)为1.158,糖原合酶激酶3β(GSK 3β)为2.273,Ib异构体血小板活化因子乙酰水解酶的α亚基(PAFAHB1)为1.889,蛋白磷酸化酶2调节亚基2 Y(PPP2R5C)为1.892,果蝇散乱基因(DVL1)为1.603,β连环蛋白(CTNNB1)为1.190,TCF7L2为1.929,这些数据与基因芯片表达水平相符；此外T2DM胰腺TCF7L2蛋白水平下调。
结论：①T2DM胰岛β细胞功能受损可能与Wnt信号通路、粘着斑、胰岛素信号通路、泛素化介导的蛋白降解通路,以及氧化磷酸化等代谢通路有关；②根据Wnt信号通路相关基因的芯片数据和PCR验证结果,推测T2DM时胰腺Wnt信号通路失调,可能处于受抑制或失活状态。TCF7L2是Wnt信号通路中的关键转录因子,TCF7L2表达水平的改变可能对其下游靶基因有重要影响,因此有待于进一步深入研究TCF7L2对全基因组转录的影响。
目的：TCF7L2为经典Wnt信号通路的关键转录因子,近来研究证实TCF7L2与T2DM发病密切相关,本研究利用染色质免疫共沉淀测序(ChIP-Seq)新技术研究TCF7L2在小鼠胰岛β细胞全基因组的结合位点,寻找TCF7L2的潜在靶基因。
方法：采用Western Blot检测小鼠胰岛β细胞株MIN6细胞的TCF7L2蛋白表达水平,氯化锂干预培养的MIN6细胞24小时,利用染色质免疫共沉淀技术(ChIP)获取TCF7L2蛋白结合的全基因组片段,利用基于solexa的新一代测序技术,在Illumina Genome AnalyzerⅡⅩ平台上对TCF7L2获得的片段产物和Input对照片段进行测序。利用eland算法将测序片段比对到小鼠的参考基因组(mm9)；用macs软件包获取TCF7L2在全基因组上的侯选结合位点；利用meme软件包计算TCF7L2的基序(motif);并利用课题组研制的软件包统计TCF7L2结合位点在全基因组上的分布；基于国家生物技术信息中心(NCBI)的基因表达数据库(GEO),分析TCF7L2与DNA结合对基因转录的影响；对启动子区有TCF7L2结合的基因利用DAVID在线工具进行功能富集分析。
结果：对TCF7L2和Input样品,利用ChIP-Seq技术,分别获得了2418万和3400万的原始序列簇(raw cluster);比对到mm9之后,分别获得了450万和1220万的特异比对片段(Unique Reads),测序错误率小于0.5%；通过生物信息学分析获得了17347个TCF7L2在全基因组上的结合位点；在这些结合位点中,有17.3%分布启动子区,有23.7%在内含子区,有2.1%在外显子区,有57.0%在基因间区；用meme软件包分析显示TCF7L2的基序为GAGA、TCTC重复序列；结合基因表达数据分析显示表达水平高的基因的转录起始位点(TSS)附近TCF7L2富集幅度低,而低表达基因富集幅度反而高；注释基因TSS±10kb内TCF7L2的候选靶基因有3600个,其中有15个明确是Wnt靶基因,有12个是已知的2型糖尿病易感基因;注释基因TSS±2kb内TCF7L2的候选靶基因有703个,KEGG代谢通路分析显示这些候选靶基因富集于丝裂原活化蛋白激酶信号通路(MAPK)、Toll样受体信号通路、Janus激酶-信号转导转录激活因子(JAK-STAT)、胰岛素信号通路、细胞周期、凋亡等20余条通路,基因本体(GO)分析显示富集于细胞分化、减数分裂细胞周期、细胞成熟、细胞周期各阶段等生物过程。
结论：在MIN6细胞中,TCF7L2蛋白主要结合在基因间区,但对启动子和内含子有更高的结合倾向；TCF7L2对基因转录有抑制也有促进作用,但以抑制占优势。TCF7L2蛋白的全基因组结合位点包含明确的Wnt靶基因和已知的糖尿病易感基因,候选的TCF7L2靶基因主要参与细胞的生长、发育,及富集于MAPK、JAK-STAT、Toll样受体等与炎症相关的代谢通路。通过对小鼠胰岛β细胞TCF7L2蛋白候选靶基因的分析,推测TCF7L2可能通过已知的糖尿病易感基因、调控胰岛β细胞的增殖和凋亡、炎症相关基因等参与糖尿病的发生发展。为了证实TCF7L2真正的靶基因,尚需进一步研究TCF7L2在胰岛β细胞中对基因转录表达的影响。
Objective:To investigate the change of gene expression profile in pancreas of patients with type 2 diabetes mellitus (T2DM); to screen differentially expressed genes in Wnt signaling pathway; and to validate the expression level of genes involved in transcription factor 7-like 2 (TCF7L2)-dependent Wnt signaling pathway.
Methods:Samples of Pancreas were obtained from the tissue bank of pathology department, Shanghai Medical College, Fudan University. We used microarray to detect 2 samples with T2DM (average age 55 years) and one without T2DM (50 years old), and used PCR to validate gene expressions for four cases with T2DM (average age 72±3.72 years) and five without T2DM (average age 52±11.1 years). Pancreas samples were isolated from each donor after death and extracted for total RNA. The cDNA microarray was hybridized using hybond membrane with 18,000 clones. After the raw array data were normalized, the differential expression of genes between diabetic and control groups was evaluated using fold change (cutoff=1.5). We performed functional enrichment analysis of KEGG (Kyoto Encyclopedia of Genes and Genomes) for these differential expressional genes with DAVID (http://david.abcc.ncifcrf.gov/) online tools. The expression level of selected genes from the Wnt signaling pathway was validated by real time quantitive PCR, and the nucleoprotein TCF7L2 was detected by the Western Blot. The statistical test of non-parametric Mann-Whiteney was used for testing the difference between the result of microarray and that of PCR.
Results:Compared with the control, there were 4200 differentially expressed genes in the gene chip of pancreas of patients with T2DM. The analysis of KEGG pathway showed that these differential expression genes were mainly enriched in more than 40 pathway including Wnt signaling pathway, focal adhesion, insulin signaling pathway, ubiquitin mediated proteolysis, oxidative phosphorylation; and there were 41 differentially expressed genes in Wnt signaling pathway, which were distributed in various branches of Wnt signaling pathway. Using quantitative PCR, in pancreas of patients with T2DM compared with non-diabetic patients, relative mRNA expression of wingless-type MMTV integration site family, member 4 (Wnt4) was 1.691, frizzled homolog 4 (FZD4) 1.158, glycogen synthase kinase 3 beta (GSK 3β) 2.273 platelet-activating factor acetylhydrolase, isoformⅠb, alpha subunit (PAFAHB1) 1.889, protein phosphatase 2, regulatory subunit B (B56), gamma isoform(PPP2R5C) 1.892, dishevelled 1(DVL1)1.603, Catenin, beta-1 (CTNNB1) 1.190 TCF7L2 1.929, which corresponded with the expression level of gene chips. In addition, the protein of TCF7L2 was decreased in pancreas of patients with T2DM.
Conclusion:Islet P-cell dysfunction in T2DM may be associated with Wnt signaling pathway, focal adhesion, insulin signaling pathway, ubiquitination-mediated protein degradation pathway, and oxidative phosphorylation et.al. Based on the expression of Wnt signaling pathway genes in microarray data and PCR results, it was supposed that the Wnt signaling was dysregulated in diabetic pancreas, and it may be inhibited or not activited. TCF7L2 is a key Wnt signaling pathway transcription factors, and the change of TCF7L2 expression may have important impact on its downstream target genes. Therefore, the effect of TCF7L2 on the whole genome transcription need to be further studied.
Objective:TCF7L2 is the key transcription factor of classical Wnt signaling pathway. Recent studies have confirmed that TCF7L2 is strongly associated with T2DM. In the study, the new chromatin immunoprecipitation sequence (ChIP-Seq) technique was used to investigate the whole genome binding sites of TCF7L2 in mouse pancreatic isletβcell in order to seek out the potential target genes of TCF7L2.
Methods:The TCF7L2 protein level was detected by Western Blot in mouse pancreaticβcell line MIN6 cell. MIN6 cell was cultured in medium with lithium chloride for 24 hours. The binding fragment of the whole genome of TCF7L2 protein was obtained by chromatin immunoprecipitation technique (ChIP). Using the new generation of sequencing technology based on Solexa, the DNA fragments of TCF7L2 obtained and Input control were sequenced on the Illumina Genome Analyzer II X platform. Then the sequenced fragments were mapped to the reference mouse genome(mm9) by Eland algorithm; the candidate binding sites of TCF7L2 in the whole genome were obtained by MACS packages; The motifs of TCF7L2 were calculated using meme package; the TCF7L2 binding sites in the genome-wide distribution were counted by package developed by our group; based on the Gene Expression Omnibus (GEO) from National Center for Biotechnology information (NCBI), the effect of the binding between TCF7L2 and DNA on the gene transcription was analyzed; these genes, whose promoter region were bound by TCF7L2 protein, were performed functional enrichment analysis using online tools of DAVID.
Results:Using ChIP-Seq,24.18 million and 34 million of the raw sequence cluster were respectively obtained in the sample immunoprecipited by TCF7L2 and Input sample; after mapping to mm9,4.5 million and 12.2 million of Unique Reads were respectively obtained, their sequencing error rates were both less than 0.5%; 17,347 binding sites of TCF7L2 protein in the whole-genome were obtained by bioinformatics analysis; 17.3%of those binding sites was distributed in promoter regions,23.7% in introns,2.1% in exons,57.0% in intergenic; The meme, a motif finding package, defined the in vivo-occupied TCF7L2-binding site as GAGA and TCTC repeat sequence; combined with gene expression data, it showed that peaks of binding sites of TCF7L2 were lower near the transcription start sites (TSS) of genes whose gene expression were higher, the peaks were high near the low expression genes; there were 3600 candidate target genes of TCF7L2 within TSS±10kb of annotated genes,15 of which were known as Wnt targeted genes, and 12 known as susceptibility gene of T2DM; there were 703 candidate target genes of TCF7L2 within TSS±2kb of annotated genes, KEGG pathway analysis revealed that those candidate target genes were enriched in more than 20 pathway, including mitogen-activated protein kinase signaling pathway (MAPK), Toll-like receptor signaling pathway, Janus kinase-signal transducer activator of transcription (JAK-STAT), insulin signaling pathway, cell cycle, apoptosis; Gene Ontology (GO) analysis showed that these genes were involved in many biological processes, such as cell differentiation, meiotic cell cycle, cell maturation, cell cycle stages.
Conclusion:In MIN6 cell, TCF7L2 protein mostly bound to intergenic, but had higher affinity with promoter and intron; it was supposed that TCF7L2 protein could inhibit and activate the gene transcription, but transcriptional inhibition may be dominant. The binding sites of TCF7L2 protein in the whole-genome included known Wnt targeted genes and diabetic susceptibility gene. The candidate target genes of TCF7L2 mostly were involved in cell growth, development and inflammation-related metabolic pathways, such as MAPK, JAK-STAT, Toll-like receptors pathway. By the analysis of candidate target gene of TCF7L2 in mouse pancreaticβcell, it was speculated that TCF7L2 may participate in the development of diabetes through those known diabetic genes, genes regulating pancreaticβcell proliferation and apoptosis, genes involved in inflammation. In order to identify true target TCF7L2 gene, further studies are needed to investigate the effect of TCF7L2 on transcription of gene expression in pancreatic islet (3 cell.
方法：胰腺组织标本来源于复旦大学上海医学院病理科组织样本库。芯片样本为2例T2DM(平均年龄55岁)和1例非糖尿病(50岁),PCR样本包括4例T2DM(72±3.72岁)和5例非糖尿病(52±11.1岁)。捐赠者死亡后迅速获取胰腺组织,抽提总RNA。应用18,000个克隆的杂交膜进行cDNA微阵列杂交。芯片数据标准化处理后,采用倍数法筛选糖尿病和非糖尿病之间的差异表达基因,阈值为1.5倍。采用DAVID (http://david. abcc. ncifcrf. gov/)在线分析工具,对差异表达基因进行日本京都基因和基因组百科全书代谢通路(KEGG pathway)功能富集分析。并用实时荧光定量PCR验证部分Wnt信号通路的基因表达,同时使用Western Blot检测核蛋白TCF7L2的水平。采用非参数Mann-Whiteney统计方法检验基因芯片结果与PCR结果的差异。
结果：基因芯片数据分析结果显示T2DM病人的胰腺差异表达基因有4200条；这些差异表达基因富集于Wnt信号通路、粘着斑、胰岛素信号通路、泛素化介导的蛋白降解通路,以及氧化磷酸化等40余条代谢通路；在Wnt信号通路中有41个差异表达基因,这些基因分布在Wnt信号通路的各个分支；定量PCR结果显示：与非糖尿病相比,T2DM胰腺Wnt4的mRNA相对表达量为1.691,Frizzled-4受体(FZD4)为1.158,糖原合酶激酶3β(GSK 3β)为2.273,Ib异构体血小板活化因子乙酰水解酶的α亚基(PAFAHB1)为1.889,蛋白磷酸化酶2调节亚基2 Y(PPP2R5C)为1.892,果蝇散乱基因(DVL1)为1.603,β连环蛋白(CTNNB1)为1.190,TCF7L2为1.929,这些数据与基因芯片表达水平相符；此外T2DM胰腺TCF7L2蛋白水平下调。
结论：①T2DM胰岛β细胞功能受损可能与Wnt信号通路、粘着斑、胰岛素信号通路、泛素化介导的蛋白降解通路,以及氧化磷酸化等代谢通路有关；②根据Wnt信号通路相关基因的芯片数据和PCR验证结果,推测T2DM时胰腺Wnt信号通路失调,可能处于受抑制或失活状态。TCF7L2是Wnt信号通路中的关键转录因子,TCF7L2表达水平的改变可能对其下游靶基因有重要影响,因此有待于进一步深入研究TCF7L2对全基因组转录的影响。
目的：TCF7L2为经典Wnt信号通路的关键转录因子,近来研究证实TCF7L2与T2DM发病密切相关,本研究利用染色质免疫共沉淀测序(ChIP-Seq)新技术研究TCF7L2在小鼠胰岛β细胞全基因组的结合位点,寻找TCF7L2的潜在靶基因。
方法：采用Western Blot检测小鼠胰岛β细胞株MIN6细胞的TCF7L2蛋白表达水平,氯化锂干预培养的MIN6细胞24小时,利用染色质免疫共沉淀技术(ChIP)获取TCF7L2蛋白结合的全基因组片段,利用基于solexa的新一代测序技术,在Illumina Genome AnalyzerⅡⅩ平台上对TCF7L2获得的片段产物和Input对照片段进行测序。利用eland算法将测序片段比对到小鼠的参考基因组(mm9)；用macs软件包获取TCF7L2在全基因组上的侯选结合位点；利用meme软件包计算TCF7L2的基序(motif);并利用课题组研制的软件包统计TCF7L2结合位点在全基因组上的分布；基于国家生物技术信息中心(NCBI)的基因表达数据库(GEO),分析TCF7L2与DNA结合对基因转录的影响；对启动子区有TCF7L2结合的基因利用DAVID在线工具进行功能富集分析。
结果：对TCF7L2和Input样品,利用ChIP-Seq技术,分别获得了2418万和3400万的原始序列簇(raw cluster);比对到mm9之后,分别获得了450万和1220万的特异比对片段(Unique Reads),测序错误率小于0.5%；通过生物信息学分析获得了17347个TCF7L2在全基因组上的结合位点；在这些结合位点中,有17.3%分布启动子区,有23.7%在内含子区,有2.1%在外显子区,有57.0%在基因间区；用meme软件包分析显示TCF7L2的基序为GAGA、TCTC重复序列；结合基因表达数据分析显示表达水平高的基因的转录起始位点(TSS)附近TCF7L2富集幅度低,而低表达基因富集幅度反而高；注释基因TSS±10kb内TCF7L2的候选靶基因有3600个,其中有15个明确是Wnt靶基因,有12个是已知的2型糖尿病易感基因;注释基因TSS±2kb内TCF7L2的候选靶基因有703个,KEGG代谢通路分析显示这些候选靶基因富集于丝裂原活化蛋白激酶信号通路(MAPK)、Toll样受体信号通路、Janus激酶-信号转导转录激活因子(JAK-STAT)、胰岛素信号通路、细胞周期、凋亡等20余条通路,基因本体(GO)分析显示富集于细胞分化、减数分裂细胞周期、细胞成熟、细胞周期各阶段等生物过程。
结论：在MIN6细胞中,TCF7L2蛋白主要结合在基因间区,但对启动子和内含子有更高的结合倾向；TCF7L2对基因转录有抑制也有促进作用,但以抑制占优势。TCF7L2蛋白的全基因组结合位点包含明确的Wnt靶基因和已知的糖尿病易感基因,候选的TCF7L2靶基因主要参与细胞的生长、发育,及富集于MAPK、JAK-STAT、Toll样受体等与炎症相关的代谢通路。通过对小鼠胰岛β细胞TCF7L2蛋白候选靶基因的分析,推测TCF7L2可能通过已知的糖尿病易感基因、调控胰岛β细胞的增殖和凋亡、炎症相关基因等参与糖尿病的发生发展。为了证实TCF7L2真正的靶基因,尚需进一步研究TCF7L2在胰岛β细胞中对基因转录表达的影响。
Objective:To investigate the change of gene expression profile in pancreas of patients with type 2 diabetes mellitus (T2DM); to screen differentially expressed genes in Wnt signaling pathway; and to validate the expression level of genes involved in transcription factor 7-like 2 (TCF7L2)-dependent Wnt signaling pathway.
Methods:Samples of Pancreas were obtained from the tissue bank of pathology department, Shanghai Medical College, Fudan University. We used microarray to detect 2 samples with T2DM (average age 55 years) and one without T2DM (50 years old), and used PCR to validate gene expressions for four cases with T2DM (average age 72±3.72 years) and five without T2DM (average age 52±11.1 years). Pancreas samples were isolated from each donor after death and extracted for total RNA. The cDNA microarray was hybridized using hybond membrane with 18,000 clones. After the raw array data were normalized, the differential expression of genes between diabetic and control groups was evaluated using fold change (cutoff=1.5). We performed functional enrichment analysis of KEGG (Kyoto Encyclopedia of Genes and Genomes) for these differential expressional genes with DAVID (http://david.abcc.ncifcrf.gov/) online tools. The expression level of selected genes from the Wnt signaling pathway was validated by real time quantitive PCR, and the nucleoprotein TCF7L2 was detected by the Western Blot. The statistical test of non-parametric Mann-Whiteney was used for testing the difference between the result of microarray and that of PCR.
Results:Compared with the control, there were 4200 differentially expressed genes in the gene chip of pancreas of patients with T2DM. The analysis of KEGG pathway showed that these differential expression genes were mainly enriched in more than 40 pathway including Wnt signaling pathway, focal adhesion, insulin signaling pathway, ubiquitin mediated proteolysis, oxidative phosphorylation; and there were 41 differentially expressed genes in Wnt signaling pathway, which were distributed in various branches of Wnt signaling pathway. Using quantitative PCR, in pancreas of patients with T2DM compared with non-diabetic patients, relative mRNA expression of wingless-type MMTV integration site family, member 4 (Wnt4) was 1.691, frizzled homolog 4 (FZD4) 1.158, glycogen synthase kinase 3 beta (GSK 3β) 2.273 platelet-activating factor acetylhydrolase, isoformⅠb, alpha subunit (PAFAHB1) 1.889, protein phosphatase 2, regulatory subunit B (B56), gamma isoform(PPP2R5C) 1.892, dishevelled 1(DVL1)1.603, Catenin, beta-1 (CTNNB1) 1.190 TCF7L2 1.929, which corresponded with the expression level of gene chips. In addition, the protein of TCF7L2 was decreased in pancreas of patients with T2DM.
Conclusion:Islet P-cell dysfunction in T2DM may be associated with Wnt signaling pathway, focal adhesion, insulin signaling pathway, ubiquitination-mediated protein degradation pathway, and oxidative phosphorylation et.al. Based on the expression of Wnt signaling pathway genes in microarray data and PCR results, it was supposed that the Wnt signaling was dysregulated in diabetic pancreas, and it may be inhibited or not activited. TCF7L2 is a key Wnt signaling pathway transcription factors, and the change of TCF7L2 expression may have important impact on its downstream target genes. Therefore, the effect of TCF7L2 on the whole genome transcription need to be further studied.
Objective:TCF7L2 is the key transcription factor of classical Wnt signaling pathway. Recent studies have confirmed that TCF7L2 is strongly associated with T2DM. In the study, the new chromatin immunoprecipitation sequence (ChIP-Seq) technique was used to investigate the whole genome binding sites of TCF7L2 in mouse pancreatic isletβcell in order to seek out the potential target genes of TCF7L2.
Methods:The TCF7L2 protein level was detected by Western Blot in mouse pancreaticβcell line MIN6 cell. MIN6 cell was cultured in medium with lithium chloride for 24 hours. The binding fragment of the whole genome of TCF7L2 protein was obtained by chromatin immunoprecipitation technique (ChIP). Using the new generation of sequencing technology based on Solexa, the DNA fragments of TCF7L2 obtained and Input control were sequenced on the Illumina Genome Analyzer II X platform. Then the sequenced fragments were mapped to the reference mouse genome(mm9) by Eland algorithm; the candidate binding sites of TCF7L2 in the whole genome were obtained by MACS packages; The motifs of TCF7L2 were calculated using meme package; the TCF7L2 binding sites in the genome-wide distribution were counted by package developed by our group; based on the Gene Expression Omnibus (GEO) from National Center for Biotechnology information (NCBI), the effect of the binding between TCF7L2 and DNA on the gene transcription was analyzed; these genes, whose promoter region were bound by TCF7L2 protein, were performed functional enrichment analysis using online tools of DAVID.
Results:Using ChIP-Seq,24.18 million and 34 million of the raw sequence cluster were respectively obtained in the sample immunoprecipited by TCF7L2 and Input sample; after mapping to mm9,4.5 million and 12.2 million of Unique Reads were respectively obtained, their sequencing error rates were both less than 0.5%; 17,347 binding sites of TCF7L2 protein in the whole-genome were obtained by bioinformatics analysis; 17.3%of those binding sites was distributed in promoter regions,23.7% in introns,2.1% in exons,57.0% in intergenic; The meme, a motif finding package, defined the in vivo-occupied TCF7L2-binding site as GAGA and TCTC repeat sequence; combined with gene expression data, it showed that peaks of binding sites of TCF7L2 were lower near the transcription start sites (TSS) of genes whose gene expression were higher, the peaks were high near the low expression genes; there were 3600 candidate target genes of TCF7L2 within TSS±10kb of annotated genes,15 of which were known as Wnt targeted genes, and 12 known as susceptibility gene of T2DM; there were 703 candidate target genes of TCF7L2 within TSS±2kb of annotated genes, KEGG pathway analysis revealed that those candidate target genes were enriched in more than 20 pathway, including mitogen-activated protein kinase signaling pathway (MAPK), Toll-like receptor signaling pathway, Janus kinase-signal transducer activator of transcription (JAK-STAT), insulin signaling pathway, cell cycle, apoptosis; Gene Ontology (GO) analysis showed that these genes were involved in many biological processes, such as cell differentiation, meiotic cell cycle, cell maturation, cell cycle stages.
Conclusion:In MIN6 cell, TCF7L2 protein mostly bound to intergenic, but had higher affinity with promoter and intron; it was supposed that TCF7L2 protein could inhibit and activate the gene transcription, but transcriptional inhibition may be dominant. The binding sites of TCF7L2 protein in the whole-genome included known Wnt targeted genes and diabetic susceptibility gene. The candidate target genes of TCF7L2 mostly were involved in cell growth, development and inflammation-related metabolic pathways, such as MAPK, JAK-STAT, Toll-like receptors pathway. By the analysis of candidate target gene of TCF7L2 in mouse pancreaticβcell, it was speculated that TCF7L2 may participate in the development of diabetes through those known diabetic genes, genes regulating pancreaticβcell proliferation and apoptosis, genes involved in inflammation. In order to identify true target TCF7L2 gene, further studies are needed to investigate the effect of TCF7L2 on transcription of gene expression in pancreatic islet (3 cell.
引文
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