Partially reprogrammed iPSCs enabled analyses of early events in XCR
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XCR initiates at a subset of genes clustered near the centromere region
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XCR occurs before complete shutoff of Xist expression during reprogramming
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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.
Graphical abstract
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.