TY - JOUR
T1 - Chromatin restriction by the nucleosome remodeler Mi-2β and functional interplay with lineage-specific transcription regulators control B-cell differentiation
AU - Yoshida, Toshimi
AU - Hu, Yeguang
AU - Zhang, Zhihong
AU - Emmanue, Akinola O.
AU - Galani, Kiriaki
AU - Muhire, Brejnev
AU - Snippert, Hugo J.
AU - Williams, Christine J.
AU - Tolstorukov, Michael Y.
AU - Gounari, Fotini
AU - Georgopoulos, Katia
N1 - Publisher Copyright:
© 2019 Yoshida et al.
PY - 2019/7
Y1 - 2019/7
N2 - Coordinated induction, but also repression, of genes are key to normal differentiation. Although the role of lineagespecific transcription regulators has been studied extensively, 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-2β, a SNF-2-like nucleosome remodeler and key component of the nucleosome remodeling and histone deacetylase (NuRD) complex in early B cells. Inactivation of Mi-2β arrested differentiation at the large pre-B-cell stage and caused derepression of cell adhesion and cell migration signaling factors by increasing chromatin access at poised enhancers and chromosome architectural elements. Mi-2β also supported IL-7R signaling, survival, and proliferation by repressing negative effectors of this pathway. Importantly, overexpression of Bcl2, a mitochondrial prosurvival gene and target of IL-7R signaling, partly rescued the differentiation block caused by Mi-2β loss. Mi-2β 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-2β shared loss-of-function cellular and molecular phenotypes with IKAROS and EBF1, albeit in a distinct fashion. Thus, the nucleosome remodeler Mi-2β promotes pre-B-cell differentiation by providing repression capabilities to distinct lineage-specific transcription factor-based regulatory networks.
AB - Coordinated induction, but also repression, of genes are key to normal differentiation. Although the role of lineagespecific transcription regulators has been studied extensively, 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-2β, a SNF-2-like nucleosome remodeler and key component of the nucleosome remodeling and histone deacetylase (NuRD) complex in early B cells. Inactivation of Mi-2β arrested differentiation at the large pre-B-cell stage and caused derepression of cell adhesion and cell migration signaling factors by increasing chromatin access at poised enhancers and chromosome architectural elements. Mi-2β also supported IL-7R signaling, survival, and proliferation by repressing negative effectors of this pathway. Importantly, overexpression of Bcl2, a mitochondrial prosurvival gene and target of IL-7R signaling, partly rescued the differentiation block caused by Mi-2β loss. Mi-2β 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-2β shared loss-of-function cellular and molecular phenotypes with IKAROS and EBF1, albeit in a distinct fashion. Thus, the nucleosome remodeler Mi-2β promotes pre-B-cell differentiation by providing repression capabilities to distinct lineage-specific transcription factor-based regulatory networks.
KW - Apoptosis
KW - Cell cycle
KW - Chromatin restriction
KW - EBF1
KW - IKAROS
KW - IL-7R signaling
KW - Metabolism
KW - Mi-2β (CHD4)
KW - NuRD
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U2 - 10.1101/gad.321901.118
DO - 10.1101/gad.321901.118
M3 - Article
C2 - 31123064
AN - SCOPUS:85069266324
SN - 0890-9369
VL - 33
SP - 763
EP - 781
JO - Genes and Development
JF - Genes and Development
IS - 13-14
ER -