Nucleosome eviction along with H3K9ac deposition enhances Sox2 binding during human neuroectodermal commitment.
Nucleosome eviction along with H3K9ac deposition enhances Sox2 binding during human neuroectodermal commitment.
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DOI：
10.1038/cdd.2017.62
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发表时间：
2017-06
影响因子：
12.4
通讯作者：
Jiang C
中科院分区：
文献类型：
--
作者：
Du Y;Liu Z;Cao X;Chen X;Chen Z;Zhang X;Zhang X;Jiang C
神经外胚层是一种重要的神经前体。然而，在人神经外胚层细胞(HNECs)从人胚胎干细胞(HESCs)分化过程中，染色质重塑及其表观遗传调控作用在很大程度上仍未被探索。在这里，我们通过从hESCs定向分化获得hNECs，并测定了这两种细胞的染色质状态。在分化过程中，H2A.Z介导的核小体耗竭导致启动子中开放的染色质结构，并上调神经外胚层基因的表达。启动子中H3K9ac信号的增加和H3K27me3信号的减少导致染色质状态活跃，激活神经外胚层基因。相反，启动子中H3K9ac信号的减少和H3K27me3信号的增加抑制了多能性基因。此外，H3K9ac信号促进多能性因子Sox2与hNECs特有的靶点结合。乙酰转移酶Kat2b的敲除会消除H3K9ac信号，破坏Sox2结合，导致分化失败。我们的结果表明，在hNECs通过染色质重塑分化为hNECs的过程中，基因表达的表观遗传调控具有层次性。
Neuroectoderm is an important neural precursor. However, chromatin remodeling and its epigenetic regulatory roles during the differentiation of human neuroectodermal cells (hNECs) from human embryonic stem cells (hESCs) remain largely unexplored. Here, we obtained hNECs through directed differentiation from hESCs, and determined chromatin states in the two cell types. Upon differentiation, H2A.Z-mediated nucleosome depletion leads to an open chromatin structure in promoters and upregulates expression of neuroectodermal genes. Increase in H3K9ac signals and decrease in H3K27me3 signals in promoters result in an active chromatin state and activate neuroectodermal genes. Conversely, decrease in H3K9ac signals and increase in H3K27me3 signals in promoters repress pluripotency genes. Moreover, H3K9ac signals facilitate the pluripotency factor Sox2 binding to target sites unique to hNECs. Knockdown of the acetyltransferase Kat2b erases H3K9ac signals, disrupts Sox2 binding, and fails the differentiation. Our results demonstrate a hierarchy of epigenetic regulation of gene expression during the differentiation of hNECs from hESCs through chromatin remodeling.