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Enhancer decommissioning by LSD1 during embryonic stem cell differentiation

机译：LSD1在胚胎干细胞分化过程中的增强子退役

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摘要

Transcription factors and chromatin modifiers are important in the programming and reprogramming of cellular states during development. Transcription factors bind to enhancer elements and recruit coactivators and chromatin-modifying enzymes to facilitate transcription initiation. During differentiation a subset of these enhancers must be silenced, but the mechanisms underlying enhancer silencing are poorly understood. Here we show that the histone demethylase lysine-specific demethylase 1 (LSD1; ref. 5), which demethylates histone H3 on Lys 4 or Lys 9 (H3K4/ K9), is essential in decommissioning enhancers during the differentiation of mouse embryonic stem cells (ESCs). LSD1 occupies enhancers of active genes that are critical for control of the state of ESCs. However, LSD1 is not essential for the maintenance of ESC identity. Instead, ESCs lacking LSD1 activity fail to differentiate fully, and ESC-specific enhancers fail to undergo the histone demethylation events associated with differentiation. At active enhancers, LSD1 is a component of the NuRD (nucleosome remodelling and histone deacetylase) complex, which contains additional subunits that are necessary for ESC differentiation. We propose that the LSD1-NuRD complex decommissions enhancers of the pluripotency program during differentiation, which is essential for the complete shutdown of the ESC gene expression program and the transition to new cell states.
机译：转录因子和染色质修饰剂在发育过程中细胞状态的编程和重编程中很重要。转录因子结合增强子元件并募集辅助激活剂和染色质修饰酶以促进转录起始。在分化过程中，必须使这些增强子的一部分沉默，但对增强子沉默的机制了解得很少。在这里，我们显示了在Lys 4或Lys 9（H3K4 / K9）上使组蛋白H3脱甲基的组蛋白脱甲基酶赖氨酸特异性脱甲基酶1（LSD1; ref.5）对于在小鼠胚胎干细胞分化过程中退役增强子至关重要（ ESCs）。 LSD1占据了激活基因的增强子，这些基因对于控制ESC的状态至关重要。但是，LSD1对于维护ESC身份并不是必需的。相反，缺少LSD1活性的ESC不能完全分化，而ESC特异性增强子则不能经历与分化相关的组蛋白去甲基化事件。在活性增强剂中，LSD1是NuRD（核小体重构和组蛋白脱乙酰基酶）复合物的组成部分，该复合物包含ESC分化所必需的其他亚基。我们建议，LSD1-NuRD复合物在分化过程中退役增强多能性程序的增强子，这对于ESC基因表达程序的完全关闭和向新细胞状态的转变至关重要。

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  • 来源
    《Nature》 |2012年第7384期|p.221-225|共5页
  • 作者

    Warren A. Whyte; Steve Bilodeau; David A. Orlando; Heather A. Hoke; Garrett M. Frampton; Charles T. Foster; Shaun M. Cowley; Richard A. Young;

  • 作者单位

    Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;

    Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;

    Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;

    Department of Molecular Biology, Adolf-Butenandt Institut, Ludwig-Maximilians-Universitat Munchen, 80336 Munich, Germany,Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK;

    Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK;

    Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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