YY1-mediated enhancer-promoter communication in the immunoglobulin μ locus is regulated by MSL/MOF recruitment
Yutthaphong Phongbunchoo,
Fatima-Zohra Braikia,
Cecilia Pessoa-Rodrigues,
Senthilkumar Ramamoorthy,
Haribaskar Ramachandran,
Anna Grosschedl,
Fei Ma,
Pierre Cauchy,
Asifa Akhtar,
Ranjan Sen,
Gerhard Mittler,
Rudolf Grosschedl
Affiliations
Yutthaphong Phongbunchoo
Laboratory of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
Fatima-Zohra Braikia
Laboratory of Molecular Biology & Immunology, National Institute on Aging, NIH, Baltimore, MD, USA
Cecilia Pessoa-Rodrigues
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
Senthilkumar Ramamoorthy
Laboratory of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Haribaskar Ramachandran
Laboratory of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
Anna Grosschedl
Laboratory of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
Fei Ma
Laboratory of Molecular Biology & Immunology, National Institute on Aging, NIH, Baltimore, MD, USA
Pierre Cauchy
Laboratory of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
Asifa Akhtar
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; Corresponding author
Ranjan Sen
Laboratory of Molecular Biology & Immunology, National Institute on Aging, NIH, Baltimore, MD, USA; Corresponding author
Gerhard Mittler
Proteomics Facility, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; Corresponding author
Rudolf Grosschedl
Laboratory of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; Corresponding author
Summary: The rearrangement and expression of the immunoglobulin μ heavy chain (Igh) gene require communication of the intragenic Eμ and 3′ regulatory region (RR) enhancers with the variable (VH) gene promoter. Eμ binding of the transcription factor YY1 has been implicated in enhancer-promoter communication, but the YY1 protein network remains obscure. By analyzing the comprehensive proteome of the 1-kb Eμ wild-type enhancer and that of Eμ lacking the YY1 binding site, we identified the male-specific lethal (MSL)/MOF complex as a component of the YY1 protein network. We found that MSL2 recruitment depends on YY1 and that gene knockout of Msl2 in primary pre-B cells reduces μ gene expression and chromatin looping of Eμ to the 3′ RR enhancer and VH promoter. Moreover, Mof heterozygosity in mice impaired μ expression and early B cell differentiation. Together, these data suggest that the MSL/MOF complex regulates Igh gene expression by augmenting YY1-mediated enhancer-promoter communication.
