Overcoming Autocrine FGF Signaling-Induced Heterogeneity in Naive Human ESCs Enables Modeling of Random X Chromosome Inactivation
Overcoming Autocrine FGF Signaling-Induced Heterogeneity in Naive Human ESCs Enables Modeling of Random X Chromosome Inactivation
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DOI：
10.1016/j.stem.2020.06.002
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发表时间：
2020
期刊：
影响因子：
23.9
通讯作者：
Haoyi Wang
中科院分区：
文献类型：
--
作者：
Chenrui An;Guihai Feng;Jixiang Zhang;Shiwei Cao;Ying Wang;Nannan Wang;Falong Lu;Qi Zhou;Haoyi Wang
Primed and naive human embryonic stem cells (hESCs) do not fully recapitulate the X chromosome status observed in human preimplantation epiblast and fail to initiate random X chromosome inactivation (XCI) upon differentiation. Therefore, an ideal system for studying XCI during early human development is yet to be established. We show that incomplete blocking of autocrine fibroblast growth factor 2 (FGF2) signaling in naive hESCs drives significant heterogeneity in X chromosome and pluripotency status. We derived homozygous XaXa naive hESCs with dual allelic XIST expression and high levels of TFCP2L1, whose transcriptome and X chromosome states are similar to human preimplantation epiblast. Random XCI was initiated upon naive-to-primed conversion of these cells, and both pre- and post-XCI primed hESCs were obtained. We observed random XCI in all cells upon further differentiation of pre-XCI primed hESCs. Together, these findings enable derivation of homogeneous naive hESCs and establish a powerful platform to study human XCI.
