Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710, USA.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27710, USA.
Nat Commun. 2022 Aug 1;13(1):4464. doi: 10.1038/s41467-022-32273-5.
X chromosome inactivation (XCI) is a dosage compensation phenomenon that occurs in females. Initiation of XCI depends on Xist RNA, which triggers silencing of one of the two X chromosomes, except for XCI escape genes that continue to be biallelically expressed. In the soma XCI is stably maintained with continuous Xist expression. How Xist impacts XCI maintenance remains an open question. Here we conditionally delete Xist in hematopoietic system of mice and report differentiation and cell cycle defects in female hematopoietic stem and progenitor cells (HSPCs). By utilizing female HSPCs and mouse embryonic fibroblasts, we find that X-linked genes show variable tolerance to Xist loss. Specifically, XCI escape genes exhibit preferential transcriptional upregulation, which associates with low H3K27me3 occupancy and high chromatin accessibility that accommodates preexisting binding of transcription factors such as Yin Yang 1 (YY1) at the basal state. We conclude that Xist is necessary for gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis.
X 染色体失活（XCI）是一种发生在女性中的剂量补偿现象。XCI 的启动依赖于 Xist RNA，它触发两条 X 染色体之一的沉默，除了 XCI 逃逸基因继续双等位基因表达。在体细胞中，XCI 随着持续的 Xist 表达而稳定维持。Xist 如何影响 XCI 的维持仍然是一个悬而未决的问题。在这里，我们在小鼠的造血系统中条件性地删除了 Xist，并报告了雌性造血干细胞和祖细胞（HSPCs）中的分化和细胞周期缺陷。通过利用雌性 HSPCs 和小鼠胚胎成纤维细胞，我们发现 X 连锁基因对 Xist 缺失具有不同的耐受能力。具体来说，XCI 逃逸基因表现出优先的转录上调，这与低 H3K27me3 占有率和高染色质可及性相关联，这些特征在基础状态下允许转录因子如 Yin Yang 1（YY1）预先结合。我们得出结论，Xist 在 XCI 维持期间对基因特异性沉默是必要的，并影响造血过程中的谱系特异性细胞分化和增殖。
