Rian基因的表达调控及与Dlk1-Dio3印记区间的关系研究
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摘要
哺乳动物基因组普遍以发育调控模式转录大量或长或短的非编码RNA(noncodingRNA,ncRNA)，其中长非编码RNA(longnoncodingRNA,lncRNA)是一类长度大于200bp的ncRNA。大量研究证据显示，它们能够参与染色质修饰，mRNA运输，pre-RNA剪切及细胞核构建等过程，从而调控基因表达。LncRNARian(NR_028261)是一个被确认的母本表达的印记基因，位于小鼠12号染色体远端的Dlk1-Dio3印记区内，跨越基因组长度约60kb，包括三个转录本Meg8，Irm和AB063319，对于它们的特性和作用还缺乏系统的认识。因此本课题以Rian基因为研究对象，主要分析其转录本在小鼠发育过程的表达模式，以及Rian基因的表达调控机制，并初步探索其在Dlk1-Dio3印记区间潜在的功能作用。
本研究首先确认Rian基因表达模式，获取着床前各阶段的胚胎，包括卵母细胞期，2-8细胞期，桑葚胚期和囊胚期，通过定量RT-PCR技术分析了Rian以及Dlk1-Dio3印记区内的相关基因的表达，结果表明Rian的三个成熟剪切转录本Meg8，Irm和AB063319以及Gtl2，Mirg和Dio3从桑葚胚期开始表达，在囊葚胚期时的表达量分别为桑胚期的2倍以上，而Dlk1在着床前却未检测到明显的表达。Rian的三个转录本的定量结果显示Irm明显高于另两个转录本，且原位杂交结果表明在囊胚的内细胞团和滋养层细胞中都可观察到Irm的信号，表明Irm在早期胚胎阶段就可能作为Rian基因的主要转录物并开始发挥功能作用。并且，我们分析了Rian在着床前的印记模式，发现影响Rian印记的Dlk1-Dio3的印记调控区（IG-DMR）在8细胞期已经是差异甲基化的，而Gtl2印记调控区（Gtl2-DMR）却是非甲基化的，说明早期发育的印记模式是通过IG-DMR建立的。在胚胎发育的中后期，Rian的三个转录本Meg8，Irm和AB063319通过原位杂交确认了它们在组织间的分布。在E10.5~E11.5全胚胎原位杂交和E15.5天的切片原位杂交实验中，它们在多个组织中存在共表达的现象，尤其是在神经，肌肉和内分泌组织。但Irm的信号主要集中在舌和骨骼肌中，并明显强于Meg8和AB063319。实时定量RT-PCR结果表明Meg8，Irm和AB063319在E12.5天，E15.5天和E18.5天的脑、舌、心、肺、肝和肾等重要器官中具有相似的表达模式，并且Irm和AB063319呈现逐渐增高的趋势，而Meg8多数脏器的表达峰值出现在E15.5天（除舌外）。在小鼠出生后和成体组织中，Rian三个转录本则只限制表达在脑，肌肉和生殖器官中，与母本表达的lncRNAGtl2和Mirg的表达非常相似，但并不与父本编码蛋白基因Dlk1和Dio3的表达完全重叠，暗示这些母本表达的lncRNA可能是被协同调控的。
其次，鉴于Rian基因具有严格的时空组织特异性表达模式，进一步对其表观遗传调控机制进行了初步研究。利用去甲基化诱导剂（5-Aza-2'-deoxycytidine,5-AZA）和去乙酰化酶抑制剂（4-phenylbutanonic acid,4-PBA）处理N2A细胞后，Rian转录本以及其同簇的lncRNAGtl2和Mirg表达明显上调（除去乙酰化酶抑制剂处理后的Gtl2）。在小鼠睾丸间充质细胞TM3和同源的癌细胞MLTC-1中，Rian的表达只出现在肿瘤细胞。通过DNA甲基化分析揭示出甲基化状态出现差异的区域在Gtl2-DMR区，而非IG-DMR或Rian-MR区。ChIP实验显示Irm转录起始位点到第一外显子长211bp序列内存在组蛋白乙酰化转移酶的结合位点。另外，通过FISH实验检测到Rian的主要转录物Irm(Rian/Irm)以核斑的形式定位于N2A和MLTC-1细胞核中，这与组织水平的亚细胞定位结果相似，而在N2A细胞中的核周也检测到Rian/Irm的信号，提示Rian在不同的细胞型中可能具有不同功能。
最后，对于Rian与Dlk1-Dio3印记区间的关系通过Rian/Irm的过表达实验进行了初步探索。在N2A细胞中瞬时过表达Rian/Irm的全长和截短体都能够一定程度抑制父源印记基因的表达，而在NIH3T3细胞中却只检测到Rian/Irm的全长序列能够部分抑制Dio3的表达。相反在N2A细胞中，过表达Rian/Irm的全长和截短体时，这一区间的母本lncRNA有表达上升的趋势，尤其是Meg8表达上调了50%左右。
综上所述，长非编码RNARian本身具有复杂的表达调控机制，在小鼠发育过程中始终维持特异的时空表达活性，并在Dlk1-Dio3印记区间内发挥表观遗传调控作用，这些结果将为进一步阐明lncRNA在胚胎发育过程和印记调控机制中的功能提供理论基础。
Currently, it has been dramatically demonstrated that pervasive mammalian genome is transcribed into long and short non-coding RNAs (ncRNAs) in a developmentally regulated pattern. Long ncRNA (lncRNA) was defined as more than200nt ncRNA, although the molecular functions of lncRNAs remained unknown, emerging evidence implicates the functional involvement of lncRNAs in the regulation of gene expression through the modification of chromatin, transport of specific mRNAs, control of pre-mRNA splicing and maintenance of subnuclear structures. LncRNA Rian gene (NR_028261) was an identified maternal expressed imprinting gene located in Dlkl-Dio3region of mouse distal chromosome12, covered approximately60kb of mouse genome, which contained three of transcripts Meg8, Irm and AB063319, but their characteristics and roles were still lack of systematical recognition. Here, we focused on Rian gene, and mainly analyzed its transcripts expression patterns across mouse development, Rian expression regulation mechanism, then preliminary explored the potential functions at Dlkl-Dio3imprinting region.
We first collected preimplanation embryos at oocyte,2-,4-,8-cell, morula and blastula stages to analyze the expression profiles of Rian and the other imprinting genes at Dlkl-Dio3. Quantitative real-time RT-PCR (QRT-PCR) results showed Meg8, Irm, AB063319, Gtl2, Mirg and Dio3all started to express at morula stage excepted for Dlk1, and their expression levels were up-regulated more than two times at blastocyst stage. The expression of Irm was obviously higher than the other two Rian transcripts, the fluorescence in situ hybridization (FISH) results showed Irm was expressed both in inner cell mass and trophoblast cells of blastula, suggesting Irm could be regarded as main transcript of Rian and functional at preimplanation stages. Alternatively, we analyzed Rian imprinted pattern at preimplanation stages, the results showed Dlkl-Dio3imprinting control region IG-DMR already maintained differentially methylated at8-cell stage, but Gt/2-DMR was still unmethylated, suggesting the imprinted pattern of the Dlkl-Dio3region was established by IG-DMR. Then, we characterized the spatiotemporal expression pattern of three mature spliced transcripts Meg8, Irm and AB0633I9of Rian gene at later-mid-gestation. The in situ hybridization results showed they were co-expressed in multi-tissues, especially in neural, muscle and endocrine tissues. However, Irm displayed more restricted expression in tongue and skeletal muscle than Meg8and AB063319. QRT-PCR results showed that Meg8, Irm and AB063319 were extremely similarly expressed in main organs including brain, tongue, heart, lung, liver and kidney during mouse development of E12.5, E15.5and E18.5. Furthermore, Rian transcripts were more restricted expressed in brain, muscle and reproductive organs in postnatal and adult mouse, which expression patterns were similar with maternal lncRNAs Gtl2and Mirg, but not overlapping with paternal coding protein genes Dlkl, suggesting these maternal lncRNAs might be coordinately regulated.
Considering Rian were regulated by strictly temporal expression specificity, we further analyzed Rian epigenetic regulation mechanism. After demethylation treatment (5-Aza-2'-deoxycytidine,5-AZA) in N2A cells, Rian, Gtl2and Mirg expression up-regulated in large degree, and Rian and Mirg expression also up-regulated by histone deacetylases inhibitor treatment (4-phenylbutanonic acid,4-PBA), but not Gtl2. Alternativly, the reason why Rian differently expressed in TM3and MLTC-1cells was mainly regulated by Gtl2-DMR methylation but not IG-DMR or Rian-MR. We also found Irm was obviously activated by histone acetylation roles at its transcription start region in MLTC-1cells by ChIP assay. Rian main transcript Irm(Rian/Irm) was mainly localized in several large speckles along with some weak staining of the nucleoplasm detected by FISH in vitro N2A and MLTC-1cells, which was similar in vivo tissues subcellular location. Of note, we also found Irm expression signals in nuclear periphery of N2A cells, suggesting Rian possibly possessed variant functions in different cell types.
At last, we preliminarily explored Rian/Irm potential functions in Dlkl-Dio3. Transient transfection assays found overexpressed full-length and truncation of Irm both inhibiting Dlkl and Dio3expression in an extent in N2A cells, but only found full-length of Irm partly inhibiting Dio3in NIH3T3cells. In contrast, we detected the expression of maternal lncRNAs were up-regulated a little in overexpression N2A cells, especially Meg8nearly increased by50%.
These results described above revealed Rian possessed complicated transcription regulated mechanism, and significant temporal expression specificity across embryonic development, implying that Rian was considered as potential functional RNA molecular in organisms, and participated in epigenetic regulations within Dlkl-Dio3imprinting region. It will supply the extent theory foundation for well understanding lncRNA function in embryonic development and genome imprinting.
本研究首先确认Rian基因表达模式，获取着床前各阶段的胚胎，包括卵母细胞期，2-8细胞期，桑葚胚期和囊胚期，通过定量RT-PCR技术分析了Rian以及Dlk1-Dio3印记区内的相关基因的表达，结果表明Rian的三个成熟剪切转录本Meg8，Irm和AB063319以及Gtl2，Mirg和Dio3从桑葚胚期开始表达，在囊葚胚期时的表达量分别为桑胚期的2倍以上，而Dlk1在着床前却未检测到明显的表达。Rian的三个转录本的定量结果显示Irm明显高于另两个转录本，且原位杂交结果表明在囊胚的内细胞团和滋养层细胞中都可观察到Irm的信号，表明Irm在早期胚胎阶段就可能作为Rian基因的主要转录物并开始发挥功能作用。并且，我们分析了Rian在着床前的印记模式，发现影响Rian印记的Dlk1-Dio3的印记调控区（IG-DMR）在8细胞期已经是差异甲基化的，而Gtl2印记调控区（Gtl2-DMR）却是非甲基化的，说明早期发育的印记模式是通过IG-DMR建立的。在胚胎发育的中后期，Rian的三个转录本Meg8，Irm和AB063319通过原位杂交确认了它们在组织间的分布。在E10.5~E11.5全胚胎原位杂交和E15.5天的切片原位杂交实验中，它们在多个组织中存在共表达的现象，尤其是在神经，肌肉和内分泌组织。但Irm的信号主要集中在舌和骨骼肌中，并明显强于Meg8和AB063319。实时定量RT-PCR结果表明Meg8，Irm和AB063319在E12.5天，E15.5天和E18.5天的脑、舌、心、肺、肝和肾等重要器官中具有相似的表达模式，并且Irm和AB063319呈现逐渐增高的趋势，而Meg8多数脏器的表达峰值出现在E15.5天（除舌外）。在小鼠出生后和成体组织中，Rian三个转录本则只限制表达在脑，肌肉和生殖器官中，与母本表达的lncRNAGtl2和Mirg的表达非常相似，但并不与父本编码蛋白基因Dlk1和Dio3的表达完全重叠，暗示这些母本表达的lncRNA可能是被协同调控的。
其次，鉴于Rian基因具有严格的时空组织特异性表达模式，进一步对其表观遗传调控机制进行了初步研究。利用去甲基化诱导剂（5-Aza-2'-deoxycytidine,5-AZA）和去乙酰化酶抑制剂（4-phenylbutanonic acid,4-PBA）处理N2A细胞后，Rian转录本以及其同簇的lncRNAGtl2和Mirg表达明显上调（除去乙酰化酶抑制剂处理后的Gtl2）。在小鼠睾丸间充质细胞TM3和同源的癌细胞MLTC-1中，Rian的表达只出现在肿瘤细胞。通过DNA甲基化分析揭示出甲基化状态出现差异的区域在Gtl2-DMR区，而非IG-DMR或Rian-MR区。ChIP实验显示Irm转录起始位点到第一外显子长211bp序列内存在组蛋白乙酰化转移酶的结合位点。另外，通过FISH实验检测到Rian的主要转录物Irm(Rian/Irm)以核斑的形式定位于N2A和MLTC-1细胞核中，这与组织水平的亚细胞定位结果相似，而在N2A细胞中的核周也检测到Rian/Irm的信号，提示Rian在不同的细胞型中可能具有不同功能。
最后，对于Rian与Dlk1-Dio3印记区间的关系通过Rian/Irm的过表达实验进行了初步探索。在N2A细胞中瞬时过表达Rian/Irm的全长和截短体都能够一定程度抑制父源印记基因的表达，而在NIH3T3细胞中却只检测到Rian/Irm的全长序列能够部分抑制Dio3的表达。相反在N2A细胞中，过表达Rian/Irm的全长和截短体时，这一区间的母本lncRNA有表达上升的趋势，尤其是Meg8表达上调了50%左右。
综上所述，长非编码RNARian本身具有复杂的表达调控机制，在小鼠发育过程中始终维持特异的时空表达活性，并在Dlk1-Dio3印记区间内发挥表观遗传调控作用，这些结果将为进一步阐明lncRNA在胚胎发育过程和印记调控机制中的功能提供理论基础。
Currently, it has been dramatically demonstrated that pervasive mammalian genome is transcribed into long and short non-coding RNAs (ncRNAs) in a developmentally regulated pattern. Long ncRNA (lncRNA) was defined as more than200nt ncRNA, although the molecular functions of lncRNAs remained unknown, emerging evidence implicates the functional involvement of lncRNAs in the regulation of gene expression through the modification of chromatin, transport of specific mRNAs, control of pre-mRNA splicing and maintenance of subnuclear structures. LncRNA Rian gene (NR_028261) was an identified maternal expressed imprinting gene located in Dlkl-Dio3region of mouse distal chromosome12, covered approximately60kb of mouse genome, which contained three of transcripts Meg8, Irm and AB063319, but their characteristics and roles were still lack of systematical recognition. Here, we focused on Rian gene, and mainly analyzed its transcripts expression patterns across mouse development, Rian expression regulation mechanism, then preliminary explored the potential functions at Dlkl-Dio3imprinting region.
We first collected preimplanation embryos at oocyte,2-,4-,8-cell, morula and blastula stages to analyze the expression profiles of Rian and the other imprinting genes at Dlkl-Dio3. Quantitative real-time RT-PCR (QRT-PCR) results showed Meg8, Irm, AB063319, Gtl2, Mirg and Dio3all started to express at morula stage excepted for Dlk1, and their expression levels were up-regulated more than two times at blastocyst stage. The expression of Irm was obviously higher than the other two Rian transcripts, the fluorescence in situ hybridization (FISH) results showed Irm was expressed both in inner cell mass and trophoblast cells of blastula, suggesting Irm could be regarded as main transcript of Rian and functional at preimplanation stages. Alternatively, we analyzed Rian imprinted pattern at preimplanation stages, the results showed Dlkl-Dio3imprinting control region IG-DMR already maintained differentially methylated at8-cell stage, but Gt/2-DMR was still unmethylated, suggesting the imprinted pattern of the Dlkl-Dio3region was established by IG-DMR. Then, we characterized the spatiotemporal expression pattern of three mature spliced transcripts Meg8, Irm and AB0633I9of Rian gene at later-mid-gestation. The in situ hybridization results showed they were co-expressed in multi-tissues, especially in neural, muscle and endocrine tissues. However, Irm displayed more restricted expression in tongue and skeletal muscle than Meg8and AB063319. QRT-PCR results showed that Meg8, Irm and AB063319 were extremely similarly expressed in main organs including brain, tongue, heart, lung, liver and kidney during mouse development of E12.5, E15.5and E18.5. Furthermore, Rian transcripts were more restricted expressed in brain, muscle and reproductive organs in postnatal and adult mouse, which expression patterns were similar with maternal lncRNAs Gtl2and Mirg, but not overlapping with paternal coding protein genes Dlkl, suggesting these maternal lncRNAs might be coordinately regulated.
Considering Rian were regulated by strictly temporal expression specificity, we further analyzed Rian epigenetic regulation mechanism. After demethylation treatment (5-Aza-2'-deoxycytidine,5-AZA) in N2A cells, Rian, Gtl2and Mirg expression up-regulated in large degree, and Rian and Mirg expression also up-regulated by histone deacetylases inhibitor treatment (4-phenylbutanonic acid,4-PBA), but not Gtl2. Alternativly, the reason why Rian differently expressed in TM3and MLTC-1cells was mainly regulated by Gtl2-DMR methylation but not IG-DMR or Rian-MR. We also found Irm was obviously activated by histone acetylation roles at its transcription start region in MLTC-1cells by ChIP assay. Rian main transcript Irm(Rian/Irm) was mainly localized in several large speckles along with some weak staining of the nucleoplasm detected by FISH in vitro N2A and MLTC-1cells, which was similar in vivo tissues subcellular location. Of note, we also found Irm expression signals in nuclear periphery of N2A cells, suggesting Rian possibly possessed variant functions in different cell types.
At last, we preliminarily explored Rian/Irm potential functions in Dlkl-Dio3. Transient transfection assays found overexpressed full-length and truncation of Irm both inhibiting Dlkl and Dio3expression in an extent in N2A cells, but only found full-length of Irm partly inhibiting Dio3in NIH3T3cells. In contrast, we detected the expression of maternal lncRNAs were up-regulated a little in overexpression N2A cells, especially Meg8nearly increased by50%.
These results described above revealed Rian possessed complicated transcription regulated mechanism, and significant temporal expression specificity across embryonic development, implying that Rian was considered as potential functional RNA molecular in organisms, and participated in epigenetic regulations within Dlkl-Dio3imprinting region. It will supply the extent theory foundation for well understanding lncRNA function in embryonic development and genome imprinting.
引文
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