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The chromatin reader ZMYND8 regulates Igh enhancers to promote immunoglobulin class switch recombination

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Item Type:Article
Title:The chromatin reader ZMYND8 regulates Igh enhancers to promote immunoglobulin class switch recombination
Creators Name:Delgado-Benito, V. and Rosen, D.B. and Wang, Q. and Gazumyan, A. and Pai, J.A. and Oliveira, T.Y. and Sundaravinayagam, D. and Zhang, W. and Andreani, M. and Keller, L. and Kieffer-Kwon, K.R. and Pękowska, A. and Jung, S. and Driesner, M. and Subbotin, R.I. and Casellas, R. and Chait, B.T. and Nussenzweig, M.C. and Di Virgilio, M.
Abstract:Class switch recombination (CSR) is a DNA recombination reaction that diversifies the effector component of antibody responses. CSR is initiated by activation-induced cytidine deaminase (AID), which targets transcriptionally active immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3' Igh super-enhancer, 3' regulatory region (3'RR), is essential for acceptor region transcription, but how this function is regulated is unknown. Here, we identify the chromatin reader ZMYND8 as an essential regulator of the 3'RR. In B cells, ZMYND8 binds promoters and super-enhancers, including the Igh enhancers. ZMYND8 controls the 3'RR activity by modulating the enhancer transcriptional status. In its absence, there is increased 3'RR polymerase loading and decreased acceptor region transcription and CSR. In addition to CSR, ZMYND8 deficiency impairs somatic hypermutation (SHM) of Igh, which is also dependent on the 3'RR. Thus, ZMYND8 controls Igh diversification in mature B lymphocytes by regulating the activity of the 3' Igh super-enhancer.
Keywords:Class Switch Recombination, Germline Transcription, Igh Super-Enhancer, 3' Regulatory Region, Somatic Hypermutation, ZMYND8, Animals, Mice
Source:Molecular Cell
Publisher:Cell Press
Page Range:636-649
Date:15 November 2018
Official Publication:https://doi.org/10.1016/j.molcel.2018.08.042
PubMed:View item in PubMed

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