Stem Cell Reports
Volume 17, Issue 1, 11 January 2022, Pages 53-67
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Article
Early reactivation of clustered genes on the inactive X chromosome during somatic cell reprogramming

https://doi.org/10.1016/j.stemcr.2021.11.008Get rights and content
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Highlights

  • Partially reprogrammed iPSCs enabled analyses of early events in XCR

  • XCR initiates at a subset of genes clustered near the centromere region

  • XCR occurs before complete shutoff of Xist expression during reprogramming

  • KDM1A inhibition appears to directly reactivate transcription from the Xi

Summary

Reprogramming of murine female somatic cells to induced pluripotent stem cells (iPSCs) is accompanied by X chromosome reactivation (XCR), by which the inactive X chromosome (Xi) in female somatic cells becomes reactivated. However, how Xi initiates reactivation during reprogramming remains poorly defined. Here, we used a Sendai virus-based reprogramming system to generate partially reprogrammed iPSCs that appear to be undergoing the initial phase of XCR. Allele-specific RNA-seq of these iPSCs revealed that XCR initiates at a subset of genes clustered near the centromere region. The initial phase of XCR occurs when the cells transit through mesenchymal-epithelial transition (MET) before complete shutoff of Xist expression. Moreover, regulatory regions of these genes display dynamic changes in lysine-demethylase 1a (KDM1A) occupancy. Our results identified clustered genes on the Xi that show reactivation in the initial phase of XCR during reprogramming and suggest a possible role for histone demethylation in this process.

Keywords

X chromosome reactivation
reprogramming
epigenetics
KDM1A

Data and code availability

The accession number for the RNA-seq and ChIP-seq datasets reported in this paper is GSE157484.

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