期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-30259-x
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资金
- NIH National Research Service [5-T32-GM07544, T32-HD079342]
- NIH NIGMS R01 Award [R01GM124571]
- NIH NICHD R01 Award [R01HD095463]
- Reproductive Science Program Pilot Grant
- University of Michigan Endowment for Basic Sciences
- University of Michigan Rackham Predoctoral Fellowship
- MStem Cell Lab Funding
- University of Michigan President's Office
- Michigan Medicine
- A. Alfred Taubman Medical Research Institute
- University of Michigan Department of Obstetrics and Gynecology
- American Society for Reproductive Medicine (ASRM) Research Institute
Cloutier et al. discovered that inhibitors of GSK3 proteins in the culture medium can reduce X-chromosome inactivation in human embryonic stem cells, leading to equal expression of X-linked genes between females and males. These findings are significant for the faithful culture of hESCs.
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. 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.
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