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首页> 外文期刊>Nature >Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells
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Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells

机译：组蛋白H3.3是胚胎干细胞内源性逆转录病毒元件沉默所必需的

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摘要

Transposable elements comprise roughly 40% of mammalian genomes(1). They have an active role in genetic variation, adaptation and evolution through the duplication or deletion of genes or their regulatory elements(2-4), and transposable elements themselves can act as alternative promoters for nearby genes, resulting in noncanonical regulation of transcription(5,6). However, transposable element activity can lead to detrimental genome instability(7), and hosts have evolved mechanisms to silence transposable element mobility appropriately(8,9). Recent studies have demonstrated that a subset of transposable elements, endogenous retroviral elements (ERVs) containing long terminal repeats (LTRs), are silenced through trimethylation of histone H3 on lysine 9 (H3K9me3) by ESET (also known as SETDB1 or KMT1E)(10) and a co-repressor complex containing KRAB-associated protein 1 (KAP1; also known as TRIM28)(11) in mouse embryonic stem cells. Here we show that the replacement histone variant H3.3 is enriched at class I and class II ERVs, notably those of the early transposon (ETn)/MusD family and intracisternal A-type particles (IAPs). Deposition at a subset of these elements is dependent upon the H3.3 chaperone complex containing alpha-thalassaemia/mental retardation syndrome X-linked (ATRX) 12 and death-domain-associated protein (DAXX)(12-14). We demonstrate that recruitment of DAXX, H3.3 and KAP1 to ERVs is co-dependent and occurs upstream of ESET, linking H3.3 to ERV-associated H3K9me3. Importantly, H3K9me3 is reduced at ERVs upon H3.3 deletion, resulting in derepression and dysregulation of adjacent, endogenous genes, along with increased retrotransposition of IAPs. Our study identifies a unique heterochromatin state marked by the presence of both H3.3 and H3K9me3, and establishes an important role for H3.3 in control of ERV retrotransposition in embryonic stem cells.
机译：转座因子约占哺乳动物基因组的40％（1）。它们通过基因或其调控元件的复制或缺失在遗传变异，适应和进化中发挥积极作用（2-4），转座因子本身可以充当附近基因的替代启动子，导致转录的非规范调控（5） ，6）。然而，转座子的活性可能导致有害的基因组不稳定（7），宿主已经进化出机制来适当地沉默转座子的迁移（8，9）。最近的研究表明，ESET（也称为SETDB1或KMT1E）通过赖氨酸9（H3K9me3）上的组蛋白H3的三甲基化作用使包含长末端重复序列（LTR）的内源性逆转录病毒元件（ERVs）的转座子子集被沉默（10）。 ）和在小鼠胚胎干细胞中包含KRAB相关蛋白1（KAP1;也称为TRIM28）（11）的共阻遏物复合物。在这里，我们显示了替代组蛋白变体H3.3在I类和II类ERV处富集，特别是早期转座子（ETn）/ MusD家族和脑池内A型颗粒（IAP）的ERV。在这些元素的子集上的沉积取决于H3.3伴侣复合物，该复合物包含α-地中海贫血/智力低下综合征X连锁（ATRX）12和死亡域相关蛋白（DAXX）（12-14）。我们证明，DAXX，H3.3和KAP1到ERV的募集是相互依赖的，并且发生在ESET的上游，将H3.3链接到与ERV相关的H3K9me3。重要的是，H3缺失后，ERV处的H3K9me3会减少，从而导致相邻内源基因的抑制和失调，以及IAP的逆转座子增加。我们的研究确定了以H3.3和H3K9me3的存在为标志的独特异染色质状态，并确立了H3.3在控制胚胎干细胞中ERV逆转座中的重要作用。

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  • 来源
    《Nature》 |2015年第7555期|240-244|共5页
  • 作者

    Elsasser Simon J.; Noh Kyung-Min; Diaz Nichole; Allis C. David; Banaszynski Laura A.;

  • 作者单位

    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, S-17121 Stockholm, Sweden|MRC Lab Mol Biol, Cambridge CB2 0QH, England;

    Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA;

    Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA;

    Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA;

    Univ Texas SW Med Ctr Dallas, Childrens Med Ctr Res Inst, Dallas, TX 75390 USA|Univ Texas SW Med Ctr Dallas, Cecil H & Ida Green Ctr Reprod Biol Sci, Dallas, TX 75390 USA|Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 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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