Unusual chromatin status and organization of the inactive X chromosome in murine trophoblast giant cells
Unusual chromatin status and organization of the inactive X chromosome in murine trophoblast giant cells
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DOI：
10.1242/dev.087429
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发表时间：
2013-02-15
期刊：
影响因子：
4.6
通讯作者：
Heard, Edith
中科院分区：
文献类型：
--
作者：
Corbel, Catherine;Diabangouaya, Patricia;Heard, Edith
哺乳动物 X 染色体失活 (XCI) 可以实现 XX 雌性和 XY 雄性之间的剂量补偿。这是一个重要的过程，XX 个体中缺乏该过程会导致主要由于胚胎外缺陷而导致早期死亡。这种对胚胎外组织中 X 连锁基因剂量的敏感性很难与报道的这些组织中 XCI 的逃逸趋势相一致。主要使用转基因或体外分化的干细胞来检查不同谱系中失活X染色体的精确转录状态，并且在植入后早期阶段，内源X连锁基因在胚胎和胚胎外谱系中沉默的程度尚不清楚。在这里，我们研究了植入后小鼠胚胎中几个基因的精确时间和谱系特异性 X 失活状态。我们发现大多数谱系中存在稳定的基因沉默，主要在一种胚胎外细胞类型：滋养层巨细胞（TGC）中具有显着水平的 XCI 逃逸。为了研究这种表观遗传不稳定性的基础，我们检查了从外胎盘锥外植体获得的 TGC 中失活 X 染色体的染色质结构和组织。我们发现 Xist RNA 包被的 X 染色体在 TGC 中具有非常不寻常的染色质含量，同时呈现异染色质标记（如 H3K27me3）和常染色质标记（如组蛋白 H4 乙酰化和 H3K4 甲基化）。引人注目的是，Xist RNA 不会在这些细胞中形成明显的沉默核区室或 Cot1 孔。这种沉默和活跃特征的不寻常组合很可能反映了 TGC 中 X 染色体的部分活性，也可能是 TGC 中 X 染色体部分活性的基础。
Mammalian X-chromosome inactivation (XCI) enables dosage compensation between XX females and XY males. It is an essential process and its absence in XX individuals results in early lethality due primarily to extra-embryonic defects. This sensitivity to X-linked gene dosage in extra-embryonic tissues is difficult to reconcile with the reported tendency of escape from XCI in these tissues. The precise transcriptional status of the inactive X chromosome in different lineages has mainly been examined using transgenes or in in vitro differentiated stem cells and the degree to which endogenous X-linked genes are silenced in embryonic and extra-embryonic lineages during early postimplantation stages is unclear. Here we investigate the precise temporal and lineage-specific X-inactivation status of several genes in postimplantation mouse embryos. We find stable gene silencing in most lineages, with significant levels of escape from XCI mainly in one extra-embryonic cell type: trophoblast giant cells (TGCs). To investigate the basis of this epigenetic instability, we examined the chromatin structure and organization of the inactive X chromosome in TGCs obtained from ectoplacental cone explants. We find that the Xist RNA-coated X chromosome has a highly unusual chromatin content in TGCs, presenting both heterochromatic marks such as H3K27me3 and euchromatic marks such as histone H4 acetylation and H3K4 methylation. Strikingly, Xist RNA does not form an overt silent nuclear compartment or Cot1 hole in these cells. This unusual combination of silent and active features is likely to reflect, and might underlie, the partial activity of the X chromosome in TGCs.