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Chromatin restriction by the nucleosome remodeler Mi-2β and functional interplay with lineage-specific transcription regulators controls B cell differentiation

ABSTRACT: Coordinated induction but also repression of genes is key to normal differentiation. Although the role of lineage-specific transcription regulators has been extensively studied, their functional integration with chromatin remodelers, one of the key enzymatic machineries that control chromatin accessibility, remains ill-defined. Here we investigate the role of Mi-2b, a SNF-2-like nucleosome remodeler and key component of the Nucleosome Remodeling Deacetylase (NuRD) complex in early B cells. Inactivation of Mi-2b arrested differentiation at the large pre-B cell stage and caused de-repression of cell adhesion and cell migration signaling factors by increasing chromatin access at poised enhancers and chromosome architectural elements. Mi-2b also supported IL-7R signaling, survival and proliferation by repressing negative effectors of this pathway. Importantly, over-expression of Bcl2, a mitochondrial pro-survival factor and target of IL-7R signaling, partly rescued the differentiation block caused by Mi-2b loss. Mi-2b stably associated with chromatin sites that harbor binding motifs for IKAROS and EBF1 and physically associated with these transcription factors both on and off chromatin. Notably, Mi-2b shared loss-of-function cellular and molecular phenotypes with IKAROS and EBF1 albeit in a distinct fashion. Thus the nucleosome remodeler Mi-2b promotes pre-B cell differentiation by providing repression capabilities to distinct lineage-specific transcription factor-based regulatory networks.

ORGANISM(S): Mus musculus

PROVIDER: GSE130315 | GEO | 2019/05/15

REPOSITORIES: GEO

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