气候变化领域集成服务门户(CCPortal): The role of HIRA-dependent H3.3 deposition and its modifications in the somatic hypermutation of immunoglobulin variable regions

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DOI	10.1073/pnas.2114743118
	The role of HIRA-dependent H3.3 deposition and its modifications in the somatic hypermutation of immunoglobulin variable regions
	Yu G.; Zhang Y.; Gupta V.; Zhang J.; MacCarthy T.; Duan Z.; Scharff M.D.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:50
英文摘要	The H3.3 histone variant and its chaperone HIRA are involved in active transcription, but their detailed roles in regulating somatic hypermutation (SHM) of immunoglobulin variable regions in human B cells are not yet fully understood. In this study, we show that the knockout (KO) of HIRA significantly decreased SHM and changed the mutation pattern of the variable region of the immunoglobulin heavy chain (IgH) in the human Ramos B cell line without changing the levels of activation-induced deaminase and other major proteins known to be involved in SHM. Except for H3K79me2/3 and Spt5, many factors related to active transcription, including H3.3, were substantively decreased in HIRA KO cells, and this was accompanied by decreased nascent transcription in the IgH locus. The abundance of ZMYND11 that specifically binds to H3.3K36me3 on the IgH locus was also reduced in the HIRA KO. Somewhat surprisingly, HIRA loss increased the chromatin accessibility of the IgH V region locus. Furthermore, stable expression of ectopic H3.3G34V and H3.3G34R mutants that inhibit both the trimethylation of H3.3K36 and the recruitment of ZMYND11 significantly reduced SHM in Ramos cells, while the H3.3K79M did not. Consistent with the HIRA KO, the H3.3G34V mutant also decreased the occupancy of various elongation factors and of ZMYND11 on the IgH variable and downstream switching regions. Our results reveal an unrecognized role of HIRA and the H3.3K36me3 modification in SHM and extend our knowledge of how transcription-associated chromatin structure and accessibility contribute to SHM in human B cells. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Chromatin accessibility; HIRA and H3.3 modifications; Immunoglobulin variable region; Somatic hypermutation; Transcription elongation
语种	英语
scopus关键词	activation induced cytidine deaminase; chaperone; histone; histone H3.3; immunoglobulin heavy chain; protein HIRA; unclassified drug; cell cycle protein; chaperone; H3-3A protein, human; HIRA protein, human; histone; transcription factor; Article; B lymphocyte; chromatin structure; controlled study; gene locus; histone modification; human; human cell; immunoglobulin class switching; immunoglobulin variable region; mutant; protein expression; Ramos cell line; somatic hypermutation; transcription initiation; upregulation; gene expression regulation; genetics; immunoglobulin variable region; metabolism; physiology; somatic hypermutation; tumor cell line; Cell Cycle Proteins; Cell Line, Tumor; Gene Expression Regulation; Histone Chaperones; Histones; Humans; Immunoglobulin Variable Region; Somatic Hypermutation, Immunoglobulin; Transcription Factors
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/250940
作者单位	Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, United States; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, United States; Department of Applied Mathematics and Statistics, Stony Brook University, Stony BrookNY 11794, United States
推荐引用方式 GB/T 7714	Yu G.,Zhang Y.,Gupta V.,et al. The role of HIRA-dependent H3.3 deposition and its modifications in the somatic hypermutation of immunoglobulin variable regions[J],2021,118(50).
APA	Yu G..,Zhang Y..,Gupta V..,Zhang J..,MacCarthy T..,...&Scharff M.D..(2021).The role of HIRA-dependent H3.3 deposition and its modifications in the somatic hypermutation of immunoglobulin variable regions.Proceedings of the National Academy of Sciences of the United States of America,118(50).
MLA	Yu G.,et al."The role of HIRA-dependent H3.3 deposition and its modifications in the somatic hypermutation of immunoglobulin variable regions".Proceedings of the National Academy of Sciences of the United States of America 118.50(2021).