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Science 329 (5994): 917-923

Copyright © 2010 by the American Association for the Advancement of Science

PTIP Promotes Chromatin Changes Critical for Immunoglobulin Class Switch Recombination

Jeremy A. Daniel,1 Margarida Almeida Santos,1,* Zhibin Wang,2,* Chongzhi Zang,3,* Kristopher R. Schwab,4 Mila Jankovic,5 Darius Filsuf,1 Hua-Tang Chen,1 Anna Gazumyan,5 Arito Yamane,6 Young-Wook Cho,7 Hong-Wei Sun,8 Kai Ge,7 Weiqun Peng,3 Michel C. Nussenzweig,5 Rafael Casellas,6 Gregory R. Dressler,4 Keji Zhao,2 André Nussenzweig1,{dagger}

Abstract: Programmed genetic rearrangements in lymphocytes require transcription at antigen receptor genes to promote accessibility for initiating double-strand break (DSB) formation critical for DNA recombination and repair. Here, we showed that activated B cells deficient in the PTIP component of the MLL3 (mixed-lineage leukemia 3)–MLL4 complex display impaired trimethylation of histone 3 at lysine 4 (H3K4me3) and transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus, leading to defective immunoglobulin class switching. We also showed that PTIP accumulation at DSBs contributes to class switch recombination (CSR) and genome stability independently of Igh switch transcription. These results demonstrate that PTIP promotes specific chromatin changes that control the accessibility of the Igh locus to CSR and suggest a nonredundant role for the MLL3-MLL4 complex in altering antibody effector function.

1 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
2 Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
3 Department of Physics, The George Washington University, Washington, DC 20052, USA.
4 Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
5 Laboratory of Molecular Immunology, The Rockefeller University, and Howard Hughes Medical Institute, New York, NY 10065, USA.
6 Genomics and Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA.
7 Nuclear Receptor Biology Section, CEB, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
8 Biodata Mining and Discovery Section, NIAMS, NIH, Bethesda, MD 20892, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: andre_nussenzweig{at}nih.gov

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