Histone h1 depletion impairs embryonic stem cell differentiation.
Histone h1 depletion impairs embryonic stem cell differentiation.
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DOI：
10.1371/journal.pgen.1002691
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Fan Y
中科院分区：
文献类型：
--
作者：
Zhang Y;Cooke M;Panjwani S;Cao K;Krauth B;Ho PY;Medrzycki M;Berhe DT;Pan C;McDevitt TC;Fan Y
众所周知，多能胚胎干细胞（ESC）拥有相对开放的染色质结构；然而，尽管人们努力描述 ESC 的染色质特征，但染色质压缩在干细胞命运和功能中的作用仍然难以捉摸。连接组蛋白 H1 对于高阶染色质折叠很重要，并且对于哺乳动物胚胎发生至关重要。为了研究 H1 和染色质压缩在干细胞多能性和分化中的作用，我们检查了多种 H1 亚型耗尽的胚胎干细胞的分化。在去除白血病抑制因子后，H1c/H1d/H1e 三无效 ESC 在贴壁单层培养物中更能抵抗自发分化。同样，大多数三重 H1 无效胚状体 (EB) 缺乏代表三个胚层的形态结构，并保留了未分化 ESC 的基因表达特征。此外，在 EB 神经分化时，三重 H1 无效细胞培养物缺乏神经突生长，并且缺乏神经标记物的有效激活。最后，我们发现与野生型对照相比，三重 H1 缺失胚胎和 EB 无法完全抑制多能性基因的表达，并且 H1 缺失会损害启动子区域的 DNA 甲基化和组蛋白标记的变化，而启动子区域是在干细胞分化和胚胎发生过程中有效沉默多能性基因 Oct4 所必需的。总之，我们证明H1在多能干细胞分化中起着关键作用，我们的结果表明H1和染色质压缩可能通过多能基因的表观遗传抑制介导多能干细胞分化。表观基因组和染色质在干细胞命运决定中发挥着关键作用。连接组蛋白 H1 是一种主要的染色质结构蛋白，可促进高级染色质折叠。通过分析缺乏多种 H1 亚型的胚胎干细胞 (ESC) 的分化能力，我们首次发现 H1 和高阶染色质压缩是多能干细胞正确分化和谱系定型所必需的。 Triple-H1 null小鼠ESC的自发分化和胚状体分化均受到损害。此外，三重 H1 缺失 ESC 的神经分化受到损害。最后，我们证明 H1 缺失会导致胚胎和 ESC 分化中多能性基因表达的有效抑制失败。我们提供的证据表明，H1 参与介导组蛋白标记和 DNA 甲基化的变化，这些变化是干细胞分化和胚胎发生过程中沉默多能性基因 Oct4 所必需的。这一发现很重要，因为它提供了一种机制联系，H1 和染色质压缩可能通过抑制多能基因表达参与多能干细胞分化。
Pluripotent embryonic stem cells (ESCs) are known to possess a relatively open chromatin structure; yet, despite efforts to characterize the chromatin signatures of ESCs, the role of chromatin compaction in stem cell fate and function remains elusive. Linker histone H1 is important for higher-order chromatin folding and is essential for mammalian embryogenesis. To investigate the role of H1 and chromatin compaction in stem cell pluripotency and differentiation, we examine the differentiation of embryonic stem cells that are depleted of multiple H1 subtypes. H1c/H1d/H1e triple null ESCs are more resistant to spontaneous differentiation in adherent monolayer culture upon removal of leukemia inhibitory factor. Similarly, the majority of the triple-H1 null embryoid bodies (EBs) lack morphological structures representing the three germ layers and retain gene expression signatures characteristic of undifferentiated ESCs. Furthermore, upon neural differentiation of EBs, triple-H1 null cell cultures are deficient in neurite outgrowth and lack efficient activation of neural markers. Finally, we discover that triple-H1 null embryos and EBs fail to fully repress the expression of the pluripotency genes in comparison with wild-type controls and that H1 depletion impairs DNA methylation and changes of histone marks at promoter regions necessary for efficiently silencing pluripotency gene Oct4 during stem cell differentiation and embryogenesis. In summary, we demonstrate that H1 plays a critical role in pluripotent stem cell differentiation, and our results suggest that H1 and chromatin compaction may mediate pluripotent stem cell differentiation through epigenetic repression of the pluripotency genes. The epigenome and chromatin play critical roles in stem cell fate determination. Linker histone H1 is a major chromatin structural protein that facilitates higher-order chromatin folding. By analyzing the differentiation capacity of embryonic stem cells (ESCs) that lack multiple H1 subtypes, we find, for the first time, that H1 and higher-order chromatin compaction are required for proper differentiation and lineage commitment of pluripotent stem cells. Triple-H1 null murine ESCs are impaired in both spontaneous differentiation and embryoid body differentiation. Furthermore, triple-H1 null ESCs are compromised in neural differentiation. Finally, we demonstrate that H1 depletion leads to failure of efficient repression of pluripotency gene expression both in embryos and in ESC differentiation. We present evidence that H1 participates in mediating changes of histone marks and DNA methylation necessary for silencing pluripotency gene Oct4 during stem cell differentiation and embryogenesis. This finding is important because it provides a mechanistic link by which H1 and chromatin compaction may participate in pluripotent stem cell differentiation through repression of pluripotency gene expression.
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