In:
PLOS ONE, Public Library of Science (PLoS), Vol. 18, No. 7 ( 2023-7-11), p. e0288005-
Abstract:
Generation of induced pluripotent stem cells from specialized cell types provides an excellent model to study how cells maintain their stability, and how they can change identity, especially in the context of disease. Previous studies have shown that chromatin safeguards cell identity by acting as a barrier to reprogramming. We investigated mechanisms by which the histone macroH2A variants inhibit reprogramming and discovered that they work as gate keepers of the mesenchymal cell state by blocking epithelial transition, a step required for reprogramming of mouse fibroblasts. More specifically, we found that individual macroH2A variants regulate the expression of defined sets of genes, whose overall function is to stabilize the mesenchymal gene expression program, thus resisting reprogramming. We identified a novel gene network (MSCN, m e s en c hymal n etwork) composed of 63 macroH2A-regulated genes related to extracellular matrix, cell membrane, signaling and the transcriptional regulators Id2 and Snai2, all of which function as guardians of the mesenchymal phenotype. ChIP-seq and KD experiments revealed a macroH2A variant-specific combinatorial targeting of the genes reconstructing the MSCN, thus generating robustness in gene expression programs to resist cellular reprogramming.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0288005
DOI:
10.1371/journal.pone.0288005.g001
DOI:
10.1371/journal.pone.0288005.g002
DOI:
10.1371/journal.pone.0288005.g003
DOI:
10.1371/journal.pone.0288005.g004
DOI:
10.1371/journal.pone.0288005.s001
DOI:
10.1371/journal.pone.0288005.s002
DOI:
10.1371/journal.pone.0288005.s003
DOI:
10.1371/journal.pone.0288005.s004
DOI:
10.1371/journal.pone.0288005.s005
DOI:
10.1371/journal.pone.0288005.s006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2267670-3
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