Preventing erosion of X-chromosome inactivation in human embryonic stem cells.
Preventing erosion of X-chromosome inactivation in human embryonic stem cells.
复制标题
防止人类胚胎干细胞 X 染色体失活的侵蚀。
DOI：
10.1038/s41467-022-30259-x
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发表时间：
2022-05-06
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
X染色体失活是表观遗传转录调控的一个范例。女性人类胚胎干细胞（hECs）在长期培养时经常会经历X失活的侵蚀。在这里，我们调查的X-失活不稳定性的来源，衍生新的引发多能人胚胎干细胞系。我们发现，培养基组成显着影响XIST lncRNA的表达，一个关键的调节X-失活。在限定的无异源培养基中培养的hESC稳定地维持XIST RNA表达和包被，而在广泛使用的mTeSR 1培养基中培养的hESC失去XIST RNA表达。我们确定mTeSR1中的氯化锂是XIST RNA丢失的原因。将氯化锂或锂靶向的GSK-3蛋白的抑制剂添加到确定的hESC培养基中阻碍了XIST RNA表达。GSK-3抑制雌性小鼠胚胎干细胞和上胚层干细胞的分化也导致XIST RNA表达的丧失。总之，这些数据可以调和观察到的hESC中X失活的变化，并为多能干细胞的忠实培养提供信息。Cloutier等人发现，用含有GSK3蛋白抑制剂的培养基培养的人胚胎干细胞（hESC）经历X染色体失活的侵蚀，这使得女性和男性之间的X连锁基因表达相等。这些发现为hESC的忠实培养提供了信息。
X-chromosome inactivation is a paradigm of epigenetic transcriptional regulation. Female human embryonic stem cells (hESCs) often undergo erosion of X-inactivation upon prolonged culture. Here, we investigate the sources of X-inactivation instability by deriving new primed pluripotent hESC lines. We find that culture media composition dramatically influenced the expression of XIST lncRNA, a key regulator of X-inactivation. hESCs cultured in a defined xenofree medium stably maintained XIST RNA expression and coating, whereas hESCs cultured in the widely used mTeSR1 medium lost XIST RNA expression. We pinpointed lithium chloride in mTeSR1 as a cause of XIST RNA loss. The addition of lithium chloride or inhibitors of GSK-3 proteins that are targeted by lithium to the defined hESC culture medium impeded XIST RNA expression. GSK-3 inhibition in differentiating female mouse embryonic stem cells and epiblast stem cells also resulted in a loss of XIST RNA expression. Together, these data may reconcile observed variations in X-inactivation in hESCs and inform the faithful culture of pluripotent stem cells. Cloutier et al. discover that human embryonic stem cells (hESCs) cultured with media containing inhibitors of GSK3 proteins undergo erosion of X-chromosome inactivation, which equalizes X-linked gene expression between females and males. The findings inform the faithful culture of hESCs.
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