Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells.
Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells.
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DOI：
10.1038/nature14345
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发表时间：
2015-06-11
期刊：
影响因子：
64.8
通讯作者：
Banaszynski LA
中科院分区：
文献类型：
--
作者：
Elsässer SJ;Noh KM;Diaz N;Allis CD;Banaszynski LA
转座因子（TE）约占哺乳动物基因组的40%。TE通过基因或其调控元件的复制或缺失在遗传变异、适应和进化中发挥了积极作用，并且TE本身可以充当附近基因的替代启动子，导致转录的非经典调控。然而，TE活动可导致有害的基因组不稳定性，并且宿主已经进化出适当沉默TE移动性的机制。最近的研究表明，TEs的一个子集，内源性逆转录病毒元件（ERVs）含有长末端重复序列（LTRs），通过ESET三甲基化组蛋白H3赖氨酸9（H3 K9 me 3）沉默（也称为SETDB 1、SET结构域分叉1或KMT 1 E）和含有KAP 1的辅阻遏物复合物（KRAB相关蛋白1，也称为含三重基序蛋白28，TRIM 28）在小鼠胚胎干细胞（ESC）中的作用。在这里，我们表明，替换组蛋白变体H3.3在I类和II类ERVs富集，特别是早期转座子（ETn）/MusD和脑池内A型颗粒（IAP）。沉积在这些元素的一个子集是依赖于H3.3分子伴侣复合物含有ATRX（α地中海贫血/精神发育迟滞综合征X）和DAXX（死亡相关蛋白6）。我们证明了DAXX、H3.3和KAP 1向ERV的募集是共同依赖的，并且是ESET的上游，将H3.3连接到ERV相关的H3 K9 me 3。重要的是，在H3.3缺失后，H3 K9 me 3在ERV处减少，导致邻近内源基因的去阻遏和失调，沿着IAP的逆转录转座增加。我们的研究确定了一种独特的异染色质状态，其特征在于H3.3和H3 K9 me 3的存在，并确定了H3.3在ESCs中ERV逆转录转座控制中的重要作用。
Transposable elements (TEs) comprise roughly forty per cent of mammalian genomes. TEs have played an active role in genetic variation, adaptation, and evolution through the duplication or deletion of genes or their regulatory elements and TEs themselves can act as alternative promoters for nearby genes resulting in non-canonical regulation of transcription. However, TE activity can lead to detrimental genome instability, and hosts have evolved mechanisms to appropriately silence TE mobility. Recent studies have demonstrated that a subset of TEs, 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, SET domain bifurcated 1, or KMT1E) and a co-repressor complex containing KAP1 (KRAB-associated protein 1, also known as tripartite motif-containing protein 28, TRIM28) in mouse embryonic stem cells (ESCs). Here we show that the replacement histone variant H3.3 is enriched at class I and class II ERVs, notably early transposon (ETn)/MusD and intracisternal A-type particles (IAPs). Deposition at a subset of these elements is dependent upon the H3.3 chaperone complex containing ATRX (alpha thalesemia/mental retardation syndrome X) and DAXX (Death-associated protein 6). We demonstrate that recruitment of DAXX, H3.3, and KAP1 to ERVs are co-dependent and 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 ESCs.