Abstract
Dosage compensation between the sexes results in one X chromosome being inactivated during female mammalian development. Chromosome-wide transcriptional silencing from the inactive X chromosome (Xi) in mammalian cells is erased in a process termed X-chromosome reactivation (XCR), which has emerged as a paradigm for studying the reversal of chromatin silencing. XCR is linked with germline development and induction of naive pluripotency in the epiblast, and also takes place upon reprogramming somatic cells to induced pluripotency. XCR depends on silencing of the long non-coding RNA (lncRNA) X inactive specific transcript (Xist) and is linked with the erasure of chromatin silencing. Over the past years, the advent of transcriptomics and epigenomics has provided new insights into the transcriptional and chromatin dynamics with which XCR takes place. However, multiple questions remain unanswered about how chromatin and transcription related processes enable XCR. Here, we review recent work on establishing the transcriptional and chromatin kinetics of XCR, as well as discuss a model by which transcription factors mediate XCR not only via Xist repression, but also by direct targeting of X-linked genes.
Highlights
X-chromosome reactivation (XCR) is a developmentally regulated process by which X-chromosome inactivation (XCI) is reversed [1,2]
When combined with other treatments such as DNA methylation and histone deacetylase (HDAC) inhibition, X inactive specific transcript (Xist) deletion increases the proportion of cells that undergoes XCR [83], again suggesting a role for Xist in contributing to maintaining long term repression of gene silencing on the Xi and preventing erosion of XCI
While early reactivating genes have expression levels comparable to late reactivating genes on the Xa [49], early reactivated genes were found to be more expressed than late reactivating genes on the Xa at day-2 of reprogramming [48]. These results strongly suggest the presence of trans factors that are induced during reprogramming and increase the expression of early genes both on the Xa and on the Xi. These results suggest that both chromatin opening and 3D chromatin organization might poise early genes for activation during induced pluripotent stem cells (iPSCs) reprogramming, possibly due to a combination of reduced Xist expression and transcription factors (TFs) overexpression, all of which remains to be functionally tested
Summary
X-chromosome reactivation (XCR) is a developmentally regulated process by which X-chromosome inactivation (XCI) is reversed [1,2]. When naive embryonic stem cells (ESCs) differentiate, random XCI is induced In mouse, another form of XCI exists and is initiated around the four-cell stage and always takes place on the paternal X chromosome, referred to as imprinted XCI [2,28,30,31,32,33]. Several events of XCR have been studied during reprograming of somatic cells into induced pluripotency, which include chromosome-wide chromatin remodeling [23,25,42,49], repression of Xist [23,25,42,48,49], loss of repressive chromatin marks [25,42], changes in 3D chromatin organization [49,50], loss of DNA methylation [25,51], gain of histone acetylation [48], gain of active RNA Polymerase II [25] and chromatin decompaction and changes in replication timing. We describe an emerging model where transcription factors including members of the pluripotency gene regulatory network target multiple regulatory elements along the Xi to reverse chromatin silencing and induce transcriptional activation during reprogramming to pluripotency
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