Histone H3.3 is required for endogenous retroviral element silencing and genome stability [RNA-Seq]

Endogenous retroviruses (ERVs) have provided an evolutionary advantage in the diversification of transcript regulation and are thought to be involved in the establishment of extraembryonic tissues during development. However, silencing of these elements remains critical for the maintenance of genome stability. Here, we define a new chromatin state that is uniquely characterized by the combination of the histone variant H3.3 and H3K9me3, two chromatin ‘marks’ that have previously been considered to belong to fundamentally opposing chromatin states. H3.3/H3K9me3 heterochromatin is fundamentally distinct from ‘canonical’ H3K9me3 heterochromatin that has been under study for decades and this unique functional interplay of a histone variant and a repressive histone mark is crucial for silencing ERVs in ESCs. Our study solidifies the emerging notion that H3.3 is not a histone variant associated exclusively with “active” chromatin and further suggests that its incorporation at unique heterochromatic regions may be central to its function during development and the maintenance of genome stability. RNA-seq analysis of three embryonic stem cell lines WT, H3.3 KO1, and H3.3 KO2)

内源性逆转录病毒（Endogenous retroviruses, ERVs）可为转录调控的多样化提供进化优势，且被认为在发育过程中参与胚外组织的建立。然而，对这类元件的沉默对于维持基因组稳定性仍至关重要。本研究界定了一种全新的染色质状态，其独特特征为组蛋白变体H3.3与H3K9me3的组合——这两种染色质标记此前被认为属于本质上对立的染色质状态。H3.3/H3K9me3异染色质与已被研究数十年的“经典”H3K9me3异染色质有着本质区别，而组蛋白变体与抑制性组蛋白标记的这一独特功能互作，对于胚胎干细胞（Embryonic Stem Cells, ESCs）中ERVs的沉默至关重要。本研究进一步巩固了新兴观点：H3.3并非仅与“活跃”染色质相关的组蛋白变体，并提示其在独特异染色质区域的掺入可能是其在发育过程中发挥功能以及维持基因组稳定性的核心机制。本研究对野生型（Wild Type, WT）、H3.3敲除1型（H3.3 KO1）及H3.3敲除2型（H3.3 KO2）共3株胚胎干细胞系开展了RNA测序（RNA-seq）分析。