Zebra fish Dnmt1 and Suv39h1 regulate organ-specific terminal differentiation during development
Zebra fish Dnmt1 and Suv39h1 regulate organ-specific terminal differentiation during development
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DOI：
10.1128/mcb.00312-06
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发表时间：
2006-10-01
影响因子：
5.3
通讯作者：
Jones, David A.
中科院分区：
文献类型：
--
作者：
Rai, Kunal;Nadauld, Lincoln D.;Jones, David A.
DNA甲基化和组蛋白甲基化是两个关键的表观遗传修饰，有助于控制异染色质的动力学。这些染色质修饰活动在指导组织特异性发育中的作用在很大程度上仍不清楚。为了解决这个问题，我们研究了DNA甲基转移酶1(DNMT1)和H3K9组蛋白甲基转移酶SUV39H1在斑马鱼发育中的作用。斑马鱼胚胎中Dnmt1基因的敲除导致肠道、外分泌胰腺和视网膜的末端分化缺陷。有趣的是，并不是所有的组织都需要DNMT1，因为肝脏和内分泌胰腺的分化似乎是正常的。正确的分化依赖于DNMT1的催化活性，因为DNMT1变种可以被活跃的斑马鱼或人DNMT1拯救，但不能被催化不活跃的衍生物拯救。DNMT1变异体显示出基因组胞嘧啶甲基化和全基因组H3K9三甲基水平的显著降低，这导致我们研究DNMT1和SUV39H1在体内功能的重叠。缺乏SUV39H1的胚胎有器官特异性末端分化缺陷，产生大量Dnmt1变异体的表型，但保留了野生型DNA甲基化水平。值得注意的是，SUV39H1的过表达挽救了Dnmt1变异体的末端分化标记。我们的结果表明，Dnmt1的活性有助于SUV39H1直接组蛋白甲基化，并且Dnmt1和SUV39H1共同帮助指导特定组织的终末分化。
DNA methylation and histone methylation are two key epigenetic modifications that help govern heterochromatin dynamics. The roles for these chromatin-modifying activities in directing tissue-specific development remain largely unknown. To address this issue, we examined the roles of DNA methyltransferase 1 (Dnmt1) and the H3K9 histone methyltransferase Suv39h1 in zebra fish development. Knockdown of Dnmt1 in zebra fish embryos caused defects in terminal differentiation of the intestine, exocrine pancreas, and retina. Interestingly, not all tissues required Dnmt1, as differentiation of the liver and endocrine pancreas appeared normal. Proper differentiation depended on Dnmt1 catalytic activity, as Dnmt1 morphants could be rescued by active zebra fish or human DNMT1 but not by catalytically inactive derivatives. Dnmt1 morphants exhibited dramatic reductions of both genomic cytosine methylation and genome-wide H3K9 trimethyl levels, leading us to investigate the overlap of in vivo functions of Dnmt1 and Suv39h1. Embryos lacking Suv39h1 had organ-specific terminal differentiation defects that produced largely phenocopies of Dnmt1 morphants but retained wild-type levels of DNA methylation. Remarkably, suv39h1 overexpression rescued markers of terminal differentiation in Dnmt1 morphants. Our results suggest that Dnmt1 activity helps direct histone methylation by Suv39h1 and that, together, Dnmt1 and Suv39h1 help guide the terminal differentiation of particular tissues.