Contiguous erosion of the inactive X in human pluripotency concludes with global DNA hypomethylation.
Contiguous erosion of the inactive X in human pluripotency concludes with global DNA hypomethylation.
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DOI：
10.1016/j.celrep.2021.109215
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发表时间：
2021-06-08
期刊：
影响因子：
8.8
通讯作者：
Pinter SF
中科院分区：
文献类型：
--
作者：
Bansal P;Ahern DT;Kondaveeti Y;Qiu CW;Pinter SF
雌性人类多能干细胞（hPSC）通常经历非活性X（Xi）侵蚀。这种关键抑制特征的逐渐丧失伴随着XIST表达的丧失，驱动X失活的长非编码RNA，并导致在侵蚀的X中沉默基因的重新激活。到目前为止，零星和渐进的侵蚀性质掩盖了其规模，动态和关键的过渡事件。为了解决这个问题，我们对数百个hPSC样本进行了DNA甲基化（DNAme）、染色质可及性和基因表达的综合分析。差异DNAme命令雌性hPSC穿过从起始到终末Xi侵蚀的轨迹。我们的研究结果确定了一个顺式调控元件XIST表达的关键，跟踪连续增长的再激活域的几个常染色质的起源，并表明，后期的DNA损伤全基因组。令人惊讶的是，从这种改变的监管格局中出现了幼稚多能性的选择特征，表明其与X剂量的联系可能在人类胚胎发育中部分保守。人类女性iPSC/ESC中沉默的X的重新激活损害了它们的效用。Bansal等人进行了一项综合基因组学分析，以揭示他们在长期培养中验证的普遍X侵蚀轨迹。从XIST丢失开始，这一轨迹表明，重新激活可能会从逃脱者连续传播到沉默的基因。
Female human pluripotent stem cells (hPSCs) routinely undergo inactive X (Xi) erosion. This progressive loss of key repressive features follows the loss of XIST expression, the long non-coding RNA driving X inactivation, and causes reactivation of silenced genes across the eroding X (Xe). To date, the sporadic and progressive nature of erosion has obscured its scale, dynamics, and key transition events. To address this problem, we perform an integrated analysis of DNA methylation (DNAme), chromatin accessibility, and gene expression across hundreds of hPSC samples. Differential DNAme orders female hPSCs across a trajectory from initiation to terminal Xi erosion. Our results identify a cis-regulatory element crucial for XIST expression, trace contiguously growing reactivated domains to a few euchromatic origins, and indicate that the late-stage Xe impairs DNAme genome-wide. Surprisingly, from this altered regulatory landscape emerge select features of naive pluripotency, suggesting that its link to X dosage may be partially conserved in human embryonic development. Reactivation of the silenced X in human female iPSC/ESCs compromises their utility. Bansal et al. perform an integrated genomics analysis to reveal a prevalent X erosion trajectory that they validate in long-term culture. Starting with XIST loss, this trajectory indicates that reactivation may spread contiguously from escapees to silenced genes.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
降低的MEK抑制可维护幼稚的人类胚胎干细胞中的基因组稳定性。
影响因子：
48
作者：
Di Stefano B;Ueda M;Sabri S;Brumbaugh J;Huebner AJ;Sahakyan A;Clement K;Clowers KJ;Erickson AR;Shioda K;Gygi SP;Gu H;Shioda T;Meissner A;Takashima Y;Plath K;Hochedlinger K
通讯作者：
Hochedlinger K
影响因子：
8.8
作者：
Bar, Shiran;Seaton, Lev Roz;Benvenisty, Nissim
通讯作者：
Benvenisty, Nissim
影响因子：
2.9
作者：
Chapman, Andrew G.;Cotton, Allison M.;Brown, Carolyn J.
通讯作者：
Brown, Carolyn J.
影响因子：
3.5
作者：
Cotton AM;Price EM;Jones MJ;Balaton BP;Kobor MS;Brown CJ
通讯作者：
Brown CJ