Combinatorial targeting of a novel MET/EMT network components by macroH2A variants safeguards cell identity [ChIP-seq]

ABSTRACT: The establishment and maintenance of cellular identity rely upon the precise coordination of regulatory pathways culminating to the proper execution of cell type-specific gene expression programs. Generation of induced pluripotent stem cells (iPSCs) from highly specialized cell types provides an excellent model system to study how cells maintain their stability through the functional interplay of transcription factors and chromatin structure, and how they can change identity, especially in the context of disease. Previous studies have shown that chromatin structure safeguards cell identity by acting as a barrier to reprogramming. Here, we investigated the mechanisms of how the histone variant macroH2A inhibits reprogramming by interfering with the mesenchyme to epithelial transition, a step that is a prerequisite for reprogramming of mouse embryonic fibroblasts. We found that each of the macroH2A isoforms regulates the expression of defined sets of genes, whose overall function is to stabilize the mesenchyme phenotype, thus resisting reprogramming. We identified a novel gene network (MSCN, mesenchyme network) composed of 63 macroH2A-regulated genes encoding proteins of the extracellular matrix, cell membrane, cytoplasmic signal integrators and the transcriptional regulators Id2 and Snai2, all of which can function as key controllers of the mesenchyme phenotype. Functional studies including ChIP-seq and KD experiments using any one of the individual macroH2A isoforms revealed an isoform-specific combinatorial targeting of the genes that reconstruct the MSCN. Our findings established that the combinatorial macroH2A targeting of the MSCN components safeguards cell identity and demonstrated its pivotal role in maintaining the differentiated cell phenotype by generating robustness in gene expression programs to resist cellular reprogramming.

ORGANISM(S): Mus musculus

PROVIDER: GSE215884 | GEO | 2023/06/21

REPOSITORIES: GEO