当前位置:科学网首页 > 小柯机器人 >详情
TET与DNMT3在多潜能干细胞中存在竞争作用
作者:小柯机器人 发布时间:2020/6/9 15:18:45

德国马克斯·普朗克分子遗传学研究所Alexander Meissner团队发现,TET与DNMT3在多潜能干细胞的大量甲基化体细胞增强子上存在竞争作用。相关论文于2020年6月8日在线发表于《自然—遗传学》。

研究人员表示,尽管表达正向(DNMT3A/B)和负向(TET1-3)的调节因子,哺乳动物细胞仍稳定地维持高水平的DNA甲基化。

研究人员使用一组基因敲除的人类胚胎干细胞系(ESC)分析了这些调节因子对DNA甲基化的单独和组合影响。DNMT3的缺失对总体甲基化水平的最大影响,包括在成千上万个正常甲基化基因座处的去甲基化。去甲基化取决于TET表达,并且仅在两个DNMT3都不存在时发生。动态基因座富含羟甲基胞嘧啶,并与一组假定的体细胞增强子重叠,这些增强子在ESC中甲基化并可以在分化时激活。

研究人员在小鼠胚胎干细胞中观察到相似的动态,这在表皮干细胞中较少见,而在体细胞组织中则几乎没有,从而表明了保守的多潜能相关机制。综上所述,这些数据揭示了多潜能细胞中大量的体细胞调节序列上,DNMT3和TET之间的竞争受到严格调控。

附:英文原文

Title: TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers

Author: Jocelyn Charlton, Eunmi J. Jung, Alexandra L. Mattei, Nina Bailly, Jing Liao, Eric J. Martin, Pay Giesselmann, Bjrn Brndl, Elena K. Stamenova, Franz-Josef Mller, Evangelos Kiskinis, Andreas Gnirke, Zachary D. Smith, Alexander Meissner

Issue&Volume: 2020-06-08

Abstract: Mammalian cells stably maintain high levels of DNA methylation despite expressing both positive (DNMT3A/B) and negative (TET1-3) regulators. Here, we analyzed the independent and combined effects of these regulators on the DNA methylation landscape using a panel of knockout human embryonic stem cell (ESC) lines. The greatest impact on global methylation levels was observed in DNMT3-deficient cells, including reproducible focal demethylation at thousands of normally methylated loci. Demethylation depends on TET expression and occurs only when both DNMT3s are absent. Dynamic loci are enriched for hydroxymethylcytosine and overlap with subsets of putative somatic enhancers that are methylated in ESCs and can be activated upon differentiation. We observe similar dynamics in mouse ESCs that were less frequent in epiblast stem cells (EpiSCs) and scarce in somatic tissues, suggesting a conserved pluripotency-linked mechanism. Taken together, our data reveal tightly regulated competition between DNMT3s and TETs at thousands of somatic regulatory sequences within pluripotent cells.

DOI: 10.1038/s41588-020-0639-9

Source: https://www.nature.com/articles/s41588-020-0639-9

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex