Title | The Chromatin Reader ZMYND8 Regulates Igh Enhancers to Promote Immunoglobulin Class Switch Recombination. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Delgado-Benito V, Rosen DB, Wang Q, Gazumyan A, Pai JA, Oliveira TY, Sundaravinayagam D, Zhang W, Andreani M, Keller L, Kieffer-Kwon K-R, Pękowska A, Jung S, Driesner M, Subbotin RI, Casellas R, Chait BT, Nussenzweig MC, Di Virgilio M |
Journal | Mol Cell |
Volume | 72 |
Issue | 4 |
Pagination | 636-649.e8 |
Date Published | 2018 11 15 |
ISSN | 1097-4164 |
Keywords | Animals, B-Lymphocytes, Cell Line, Chromatin, Chromatin Assembly and Disassembly, Cytidine Deaminase, DNA, Enhancer Elements, Genetic, Gene Rearrangement, Humans, Immunoglobulin Class Switching, Immunoglobulin Heavy Chains, Mice, Mice, Inbred C57BL, MYND Domains, Promoter Regions, Genetic, Regulatory Sequences, Nucleic Acid, Somatic Hypermutation, Immunoglobulin, Tumor Suppressor Proteins |
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. |
DOI | 10.1016/j.molcel.2018.08.042 |
Alternate Journal | Mol. Cell |
PubMed ID | 30293785 |
PubMed Central ID | PMC6242708 |
Grant List | R01 AI037526 / AI / NIAID NIH HHS / United States P41 GM103314 / GM / NIGMS NIH HHS / United States R37 AI037526 / AI / NIAID NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States P41 GM109824 / GM / NIGMS NIH HHS / United States / HHMI / Howard Hughes Medical Institute / United States |
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