The Histone Variant MacroH2A Blocks Cellular Reprogramming by Inhibiting Mesenchymal-to-Epithelial Transition

Molecular and Cellular Biology
Maria PliatskaDimitris Thanos

Abstract

Transcription factor-induced reprogramming of somatic cells to pluripotency is mediated via profound alterations in the epigenetic landscape. The histone variant macroH2A1 (mH2A1) is a barrier to the cellular reprogramming process. We demonstrate here that mH2A1 blocks reprogramming and contributes to the preservation of cell identity by trapping cells at the very early stages of the process, namely, at the mesenchymal-to-epithelial transition (MET). We provide a comprehensive analysis of the genomic sites occupied by the mH2A1 nucleosomes in human fibroblasts and embryonic stem (ES) cells and how they affect the reprogramming of fibroblasts to pluripotency. We have integrated chromatin immunoprecipitation sequencing (ChIP-seq) data with transcriptome sequencing (RNA-seq) data using cells containing reduced levels of mH2A1 and have inferred mH2A1-centered gene-regulatory networks that support the fibroblast and ES cell fates. We found that the exact positions of mH2A1 nucleosomes in regulatory regions of specific network genes with key regulatory roles guarantee the functional robustness of the regulatory networks. Using the reconstructed networks, we can predict and validate several components and their interactions in the est...Continue Reading

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Citations

Sep 1, 2018·Epigenetics : Official Journal of the DNA Methylation Society·Oriana Lo ReManlio Vinciguerra
Jun 23, 2020·Antioxidants & Redox Signaling·Sebastiano GiallongoManlio Vinciguerra
Mar 20, 2019·Nature Reviews. Genetics·Paul B TalbertSteven Henikoff
Nov 24, 2019·Stem Cell Reviews and Reports·Krishna Kumar HaridhasapavalanRajkumar P Thummer
Nov 7, 2019·Molecular Cancer Research : MCR·Huan WangXiaojing Ma
Nov 21, 2020·Cells·Imtiaz Nisar LoneHani Alotaibi
Mar 28, 2021·Journal of Cell Science·Paul B Talbert, Steven Henikoff

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