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
Affiliations
Xiangdong Lu
The Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA
Chi-Shuen Chu
The Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA
Terry Fang
The Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065, USA
Violeta Rayon-Estrada
The Laboratory of Lymphocyte Biology, The Rockefeller University, New York, NY 10065, USA
Fang Fang
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
Alina Patke
The Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065, USA
Ye Qian
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Stephen H. Clarke
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Ari M. Melnick
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
Yi Zhang
HHMI, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
F. Nina Papavasiliou
The Laboratory of Lymphocyte Biology, The Rockefeller University, New York, NY 10065, USA; Division of Immune Diversity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
Robert G. Roeder
The Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA; Corresponding author
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
