Hierarchical Accumulation of Histone Variant H2A.Z Regulates Transcriptional States and Histone Modifications in Early Mammalian Embryos.
Hierarchical Accumulation of Histone Variant H2A.Z Regulates Transcriptional States and Histone Modifications in Early Mammalian Embryos.
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组蛋白变体 H2A.Z 的分层积累调节早期哺乳动物胚胎中的转录状态和组蛋白修饰
DOI：
10.1002/advs.202200057
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发表时间：
2022-08
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早期胚胎经历广泛的表观遗传重编程以实现配子到胚胎的转变，这涉及染色质上组蛋白变体H2A.Z的加载和去除。然而，H2A.Z如何在植入前发育过程中调节基因表达和组蛋白修饰仍然没有揭示。在这里，通过使用超低输入天然染色质免疫沉淀和测序，在小鼠卵母细胞和早期胚胎中描绘了H2A.Z的全基因组分布。这些景观表明，父本H2A.Z在受精后被去除，随后在合子基因组激活（ZGA）期间在亲本基因组上无偏积累。值得注意的是，H2A.Z在启动子处表现出不同峰类型的分级积累：具有双H2A.Z峰的启动子与H3 K4 me 3共定位，表明转录激活;具有单个H2A.Z峰的启动子更可能占据二价标记（H3 K4 me 3 + H3 K27 me 3），表明发育基因抑制;没有H2A.Z积累的启动子在早期胚胎中表现出持续的基因沉默。此外，H2A.Z耗竭改变了组蛋白修饰和RNA聚合酶II在启动子处结合的富集，导致谱系定型期间的异常基因表达和发育停滞。此外，小鼠和猪胚胎之间类似的转录和积累模式表明，在哺乳动物植入前发育过程中，H2A.Z在调节适当基因表达所需的表观基因组中的双重作用是保守的。作者描绘了小鼠卵母细胞和早期胚胎中的H2 A. Z景观，并意外地将其在合子基因组激活期间在染色质上的两种掺入模式鉴定为双峰和单峰。启动子H2A.Z的这种分级积累表明其在诱导植入前发育过程中基因表达调控的局部表观遗传变化中的双重作用。
Early embryos undergo extensive epigenetic reprogramming to achieve gamete‐to‐embryo transition, which involves the loading and removal of histone variant H2A.Z on chromatin. However, how does H2A.Z regulate gene expression and histone modifications during preimplantation development remains unrevealed. Here, by using ultra‐low‐input native chromatin immunoprecipitation and sequencing, the genome‐wide distribution of H2A.Z is delineated in mouse oocytes and early embryos. These landscapes indicate that paternal H2A.Z is removed upon fertilization, followed by unbiased accumulation on parental genomes during zygotic genome activation (ZGA). Remarkably, H2A.Z exhibits hierarchical accumulation as different peak types at promoters: promoters with double H2A.Z peaks are colocalized with H3K4me3 and indicate transcriptional activation; promoters with a single H2A.Z peak are more likely to occupy bivalent marks (H3K4me3+H3K27me3) and indicate development gene suppression; promoters with no H2A.Z accumulation exhibit persisting gene silencing in early embryos. Moreover, H2A.Z depletion changes the enrichment of histone modifications and RNA polymerase II binding at promoters, resulting in abnormal gene expression and developmental arrest during lineage commitment. Furthermore, similar transcription and accumulation patterns between mouse and porcine embryos indicate that a dual role of H2A.Z in regulating the epigenome required for proper gene expression is conserved during mammalian preimplantation development. The authors delineate the H2A.Z landscapes in mouse oocytes and early embryos and unexpectedly identify its two incorporation modes on chromatin during zygotic genome activation as double and single peaks. This hierarchical accumulation of promoter H2A.Z indicates its dual role in inducing the local epigenetic changes for gene expression regulation during preimplantation development.