Dynamic reversal of random X-Chromosome inactivation during iPSC reprogramming
| Autor: | San Kit To, Adrian Janiszewski, Irene Talon, Juan Song, Greet Bervoets, Natalie De Geest, Jean-Christophe Marine, Joel Chappell, Florian Rambow, Lotte Vanheer, Caterina Provenzano, Oskar Marín-Béjar, Vincent Pasque, Samuel Collombet |
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| Rok vydání: | 2019 |
| Předmět: |
Transcriptional Activation
X Chromosome Induced Pluripotent Stem Cells Chromatin silencing Biology Histone Deacetylases X-inactivation Mice 03 medical and health sciences 0302 clinical medicine Genes X-Linked X Chromosome Inactivation Genetics Animals Gene silencing Gene Silencing Induced pluripotent stem cell Genetics (clinical) Tissue homeostasis 030304 developmental biology Regulation of gene expression 0303 health sciences Research Cellular Reprogramming Chromatin Cell biology Female RNA Long Noncoding Reprogramming 030217 neurology & neurosurgery |
| Zdroj: | Genome Research. 29:1659-1672 |
| ISSN: | 1549-5469 1088-9051 |
| Popis: | Induction and reversal of chromatin silencing is critical for successful development, tissue homeostasis, and the derivation of induced pluripotent stem cells (iPSCs). X-Chromosome inactivation (XCI) and reactivation (XCR) in female cells represent chromosome-wide transitions between active and inactive chromatin states. Although XCI has long been studied, providing important insights into gene regulation, the dynamics and mechanisms underlying the reversal of stable chromatin silencing of X-linked genes are much less understood. Here, we use allele-specific transcriptomics to study XCR during mouse iPSC reprogramming in order to elucidate the timing and mechanisms of chromosome-wide reversal of gene silencing. We show that XCR is hierarchical, with subsets of genes reactivating early, late, and very late during reprogramming. Early genes are activated before the onset of late pluripotency genes activation. Early genes are located genomically closer to genes that escape XCI, unlike genes reactivating late. Early genes also show increased pluripotency transcription factor (TF) binding. We also reveal that histone deacetylases (HDACs) restrict XCR in reprogramming intermediates and that the severe hypoacetylation state of the inactive X Chromosome (Xi) persists until late reprogramming stages. Altogether, these results reveal the timing of transcriptional activation of monoallelically repressed genes during iPSC reprogramming, and suggest that allelic activation involves the combined action of chromatin topology, pluripotency TFs, and chromatin regulators. These findings are important for our understanding of gene silencing, maintenance of cell identity, reprogramming, and disease. ispartof: Genome Research vol:29 issue:10 pages:1659-1672 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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