Maternal DNA Methylation Regulates Early Trophoblast Development.
Maternal DNA Methylation Regulates Early Trophoblast Development.
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DOI：
10.1016/j.devcel.2015.12.027
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发表时间：
2016-01-25
影响因子：
11.8
通讯作者：
Reik W
中科院分区：
文献类型：
--
作者：
Branco MR;King M;Perez-Garcia V;Bogutz AB;Caley M;Fineberg E;Lefebvre L;Cook SJ;Dean W;Hemberger M;Reik W
DNA甲基化在胚胎发育中的关键作用已经很好地建立，但对其在滋养层发育中的作用知之甚少，滋养层是产生胎盘的胚外谱系。我们通过对Dnmt 3a/3b突变体进行mRNA和DNA甲基化分析，剖析了DNA甲基化在滋养层发育中的作用。我们发现，卵母细胞衍生的甲基化在调节滋养层发育中起着重要作用，但关键的胎盘调节因子Ascl 2的印迹仅部分负责这些作用。我们已经确定了几个甲基化调控基因与滋养层分化，参与细胞粘附和迁移，可能影响滋养层入侵。具体地，滋养层特异性DNA甲基化与Scml 2的沉默有关，Scml 2是一种多梳抑制复合物1蛋白，其驱动甲基化缺陷滋养层中细胞粘附的丧失。我们的研究结果表明，母体DNA甲基化控制多个分化相关的滋养层细胞的生理过程，通过印记依赖和非依赖的机制。卵母细胞衍生的DNA甲基化是滋养层转录的重要调节因子DNA甲基化控制滋养层细胞粘附Polycomb基因Scml 2的沉默是正常滋养层发育所必需的Branco et al.通过对甲基化缺陷突变体的全基因组分析，剖析DNA甲基化在小鼠滋养层发育中的作用。从卵母细胞携带的DNA甲基化标记在滋养层发育和细胞粘附中起主要作用，这部分依赖于Polycomb基因Scml 2的沉默。
Critical roles for DNA methylation in embryonic development are well established, but less is known about its roles during trophoblast development, the extraembryonic lineage that gives rise to the placenta. We dissected the role of DNA methylation in trophoblast development by performing mRNA and DNA methylation profiling of Dnmt3a/3b mutants. We find that oocyte-derived methylation plays a major role in regulating trophoblast development but that imprinting of the key placental regulator Ascl2 is only partially responsible for these effects. We have identified several methylation-regulated genes associated with trophoblast differentiation that are involved in cell adhesion and migration, potentially affecting trophoblast invasion. Specifically, trophoblast-specific DNA methylation is linked to the silencing of Scml2, a Polycomb Repressive Complex 1 protein that drives loss of cell adhesion in methylation-deficient trophoblast. Our results reveal that maternal DNA methylation controls multiple differentiation-related and physiological processes in trophoblast via both imprinting-dependent and -independent mechanisms. Oocyte-derived DNA methylation is an important regulator of trophoblast transcription DNA methylation controls trophoblast cell adhesion Silencing of Polycomb gene Scml2 is necessary for normal trophoblast development Branco et al. dissect the role of DNA methylation in mouse trophoblast development through genome-wide profiling of methylation-deficient mutants. DNA methylation marks carried over from the oocyte play a major role in trophoblast development and cell adhesion, which is partly dependent on silencing of the Polycomb gene Scml2.