Cell Reports (Jul 2019)

MTA2/NuRD Regulates B Cell Development and Cooperates with OCA-B in Controlling the Pre-B to Immature B Cell Transition

  • Xiangdong Lu,
  • Chi-Shuen Chu,
  • Terry Fang,
  • Violeta Rayon-Estrada,
  • Fang Fang,
  • Alina Patke,
  • Ye Qian,
  • Stephen H. Clarke,
  • Ari M. Melnick,
  • Yi Zhang,
  • F. Nina Papavasiliou,
  • Robert G. Roeder

Journal volume & issue
Vol. 28, no. 2
pp. 472 – 485.e5

Abstract

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Summary: The NuRD complex contains both chromatin remodeling and histone deacetylase activities. Mice lacking the MTA2 subunit of NuRD show developmental defects in pro-B, pre-B, immature B, and marginal zone B cells, and abnormal germinal center B cell differentiation during immune responses. Mta2 inactivation also causes a derepression of Igll1 and VpreB1 genes in pre-B cells. Furthermore, MTA2/NuRD interacts directly with AIOLOS/IKAROS and shows a striking overlap with AIOLOS/IKAROS target genes in human pre-B cells, suggesting a functional inter-dependence between MTA2/NuRD and AIOLOS. Mechanistically, MTA2 deficiency in mice leads to increased H3K27 acetylation at both Igll1 and VpreB1 promoters. Gene profiling analyses also identify distinct MTA2-dependent transcription programs in pro-B and pre-B cells. In addition, we find a strong synergy between MTA2 and OCA-B in repressing Igll1 and VpreB1 at the pre-B cell stage, and in regulating both the pre-B to immature B transition and splenic B cell development. : Lu et al. examine B cell developmental defects in MTA2-deficient mice. MTA2 interacts with AIOLOS/IKAROS, represses Igll1 expression, co-binds to most AIOLOS/IKAROS target genes in pre-B cells, and cooperates with OCA-B in the pre-B to immature B transition. These data suggest that AIOLOS/IKAROS functions through MTA2/NuRD during B cell development. Keywords: MTA2, NuRD, B cell development, OCA-B, chromatin, transcriptional regulation, epigenetics, AIOLOS, Igll1, pre-B cell