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TRIM28在绵羊成纤维细胞增殖过程中通过不同机制调节Igf2 - H19和Dlk1 - Gtl2印记。

TRIM28 regulates Igf2-H19 and Dlk1-Gtl2 imprinting by distinct mechanisms during sheep fibroblast proliferation.

作者信息

Luo Jian, Zhang Yiyuan, Guo Yanhua, Tang Hong, Wei Haixia, Liu Shouren, Wang Xinhua, Wang Limin, Zhou Ping

机构信息

Key Laboratory for Sheep Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Science, 221 Wuyi Road, Shihezi, Xinjiang 832000, China.

Key Laboratory for Sheep Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Science, 221 Wuyi Road, Shihezi, Xinjiang 832000, China; College of Animal Science and Technology, Shihezi University, Shihezi, Xinjiang 832003, China.

出版信息

Gene. 2017 Dec 30;637:152-160. doi: 10.1016/j.gene.2017.09.048. Epub 2017 Sep 23.

Abstract

DNA methylation is an essential epigenetic modification involved in regulating gene expression and maintaining epigenetic information across generations. However, how these marks are recognized and interpreted to activate or repress imprinted genes is not fully understood. Preliminary evidence describes the transcriptional repressor TRIM28 as a key regulator of imprinted gene expression during and after early genome-wide reprogramming. Aberrant expression of imprinted genes maybe one possible cause of incomplete epigenetic reprogramming and low efficiency in somatic cell nuclear transfer. Here, we perform a series of experiments to determine whether knockdown of Trim28 alters imprinted gene expression and DMR methylation in sheep embryonic fibroblast (SEF) cells. siRNA-mediated Trim28 silencing in SEF cells resulted in significantly decreased expression of Gtl2 to 30% and increased expression of Dlk1 (~1.7-fold). Moreover, knocking down Trim28 induced DNA methylation at the IG-DMR and the Gtl2 promoter was disrupted. Here, we uncover an important role for Trim28 in the maintenance of DNA methylation at IG-DMR during replication-dependent dilution of methylated cytosine during cellular proliferation. Unlike Dlk1-Gtl2 however, knocking down Trim28 does not affect DMR methylation in the Igf2-H19 gene cluster, yet results in increased expression of Igf2 and H19. Interestingly, Peg3 expression decreased by 60% in Trim28 knockdown cells. PEG3 as a transcriptional repressor to the H19-ICR that interacts with the co-repressor protein TRIM28 through KRAB-A. Trim28 therefore appears to control the Igf2-H19 imprinted cluster indirectly via PEG3, which is distinct from its classical role in preserving DNA methylation during DNA replication. Our results therefore indicate that Trim28 regulates imprinted gene expression through at least two distinct mechanisms during cells proliferation.

摘要

DNA甲基化是一种重要的表观遗传修饰,参与调节基因表达并在世代间维持表观遗传信息。然而,这些标记如何被识别和解读以激活或抑制印记基因,目前尚未完全清楚。初步证据表明,转录抑制因子TRIM28是早期全基因组重编程期间及之后印记基因表达的关键调节因子。印记基因的异常表达可能是体细胞重编程不完全和体细胞核移植效率低下的一个可能原因。在这里,我们进行了一系列实验,以确定敲低Trim28是否会改变绵羊胚胎成纤维细胞(SEF)中印记基因的表达和DMR甲基化。siRNA介导的SEF细胞中Trim28沉默导致Gtl2表达显著降低至30%,Dlk1表达增加(约1.7倍)。此外,敲低Trim28会诱导IG-DMR处的DNA甲基化,Gtl2启动子被破坏。在这里,我们发现Trim28在细胞增殖过程中甲基化胞嘧啶的复制依赖性稀释期间,对IG-DMR处DNA甲基化的维持起着重要作用。然而,与Dlk1-Gtl2不同,敲低Trim28不会影响Igf2-H19基因簇中的DMR甲基化,但会导致Igf2和H19表达增加。有趣的是,在Trim28敲低的细胞中,Peg3表达下降了60%。PEG3作为H19-ICR的转录抑制因子,通过KRAB-A与共抑制蛋白TRIM28相互作用。因此,Trim28似乎通过PEG3间接控制Igf2-H19印记簇,这与其在DNA复制过程中保留DNA甲基化的经典作用不同。因此,我们的结果表明,Trim28在细胞增殖过程中通过至少两种不同的机制调节印记基因的表达。

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