DNA Methylation Profiles Define Stem Cell Identity and Reveal a Tight Embryonic-Extraembryonic Lineage Boundary
DNA Methylation Profiles Define Stem Cell Identity and Reveal a Tight Embryonic-Extraembryonic Lineage Boundary
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DOI：
10.1002/stem.1249
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发表时间：
2012-12-01
期刊：
影响因子：
5.2
通讯作者：
Hemberger, Myriam
中科院分区：
文献类型：
--
作者：
Senner, Claire E.;Krueger, Felix;Hemberger, Myriam
胚胎干细胞（ES）和外胚层干细胞（EpiSC）是多能干细胞，但致力于胚胎谱系的命运。相反，滋养细胞（TS）和胚胎外内胚层（XEN）干细胞分别在胎盘和卵黄囊组织中起主要作用。在这里，我们展示了这四种干细胞类型中的每一种都是由独特的DNA甲基化谱定义的。尽管它们的发育起源不同，TS和XEN细胞共享关键的表观基因组特征，主要特征是胚胎特异性发育调节因子的强大DNA甲基化，以及5-羟甲基化的从属作用。我们还观察到，与体内组织相比，胚胎外干细胞中预先存在的表观遗传抑制标记存在大量甲基化强化，这可能是由于Dnmt3b持续高表达水平所致。这些差异在胚胎干细胞和胚胎外干细胞类型之间建立了一个主要的表观遗传屏障。此外，表观遗传谱系边界还通过相互抑制关键谱系特异性转录因子来分离两种胚胎外干细胞类型。因此，全球DNA甲基化模式是每种干细胞类型的一个决定性特征，它支持谱系承诺和早期胚胎源性干细胞的分化效力。我们详细的甲基化图谱确定了一组发育调节序列元件，如孤儿CpG岛，这将是最有价值的发现新的转录调节因子和多能性和谱系分化中的关键“看门人”基因。干细胞2012；30: 2732 - 2745
Embryonic (ES) and epiblast (EpiSC) stem cells are pluripotent but committed to an embryonic lineage fate. Conversely, trophoblast (TS) and extraembryonic endoderm (XEN) stem cells contribute predominantly to tissues of the placenta and yolk sac, respectively. Here we show that each of these four stem cell types is defined by a unique DNA methylation profile. Despite their distinct developmental origin, TS and XEN cells share key epigenomic hallmarks, chiefly characterized by robust DNA methylation of embryo-specific developmental regulators, as well as a subordinate role of 5-hydroxymethylation. We also observe a substantial methylation reinforcement of pre-existing epigenetic repressive marks that specifically occurs in extraembryonic stem cells compared to in vivo tissue, presumably due to continued high Dnmt3b expression levels. These differences establish a major epigenetic barrier between the embryonic and extraembryonic stem cell types. In addition, epigenetic lineage boundaries also separate the two extraembryonic stem cell types by mutual repression of key lineagespecific transcription factors. Thus, global DNA methylation patterns are a defining feature of each stem cell type that underpin lineage commitment and differentiative potency of early embryo-derived stem cells. Our detailed methylation profiles identify a cohort of developmentally regulated sequence elements, such as orphan CpG islands, that will be most valuable to uncover novel transcriptional regulators and pivotal "gatekeeper'' genes in pluripotency and lineage differentiation. STEM CELLS 2012; 30: 2732-2745