The role of HIRA-dependent H3.3 deposition and its modifications in the somatic hypermutation of immunoglobulin variable regions.
HIRA and H3.3 modifications
chromatin accessibility
immunoglobulin variable region
somatic hypermutation
transcription elongation
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
14 12 2021
14 12 2021
Historique:
accepted:
27
10
2021
entrez:
7
12
2021
pubmed:
8
12
2021
medline:
11
1
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34873043
pii: 2114743118
doi: 10.1073/pnas.2114743118
pmc: PMC8685899
pii:
doi:
Substances chimiques
Cell Cycle Proteins
0
H3-3A protein, human
0
HIRA protein, human
0
Histone Chaperones
0
Histones
0
Immunoglobulin Variable Region
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R01 AI132507
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no competing interest.
Références
J Biol Chem. 2011 Jul 15;286(28):24931-42
pubmed: 21572036
Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):9598-9603
pubmed: 30181289
Adv Immunol. 2015;127:257-308
pubmed: 26073986
J Exp Med. 2007 Jan 22;204(1):181-90
pubmed: 17227912
Mol Cell. 2017 Jan 19;65(2):272-284
pubmed: 28107649
Trends Immunol. 2020 Jul;41(7):586-600
pubmed: 32434680
Proc Natl Acad Sci U S A. 2013 May 7;110(19):7784-9
pubmed: 23610419
Annu Rev Genet. 2018 Nov 23;52:109-130
pubmed: 30183406
Cell. 2010 Mar 5;140(5):678-91
pubmed: 20211137
EMBO J. 2016 Jul 1;35(13):1452-64
pubmed: 27220848
Immunity. 2007 Nov;27(5):711-22
pubmed: 17980632
Cancer Cell. 2013 May 13;23(5):677-92
pubmed: 23680150
J Immunol. 2014 Jul 1;193(1):252-7
pubmed: 24879790
Immunity. 2020 Nov 17;53(5):952-970.e11
pubmed: 33098766
Nat Commun. 2014 Jun 13;5:4137
pubmed: 24923561
Nat Commun. 2018 Mar 28;9(1):1248
pubmed: 29593215
Nucleic Acids Res. 2019 Nov 18;47(20):10815-10829
pubmed: 31566237
J Immunol. 2011 Sep 1;187(5):2464-75
pubmed: 21804017
PLoS Genet. 2012 Feb;8(2):e1002518
pubmed: 22346767
Front Immunol. 2020 Apr 30;11:788
pubmed: 32425948
Nature. 2014 Apr 10;508(7495):263-8
pubmed: 24590075
Cell. 2013 Sep 26;155(1):107-20
pubmed: 24074864
Mol Cell. 2017 Aug 3;67(3):361-373.e4
pubmed: 28757211
Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18667-72
pubmed: 25512519
Eur J Immunol. 2020 Mar;50(3):380-395
pubmed: 31821534
Science. 2013 May 17;340(6134):857-61
pubmed: 23539183
J Exp Med. 1990 Dec 1;172(6):1717-27
pubmed: 2258702
Transcription. 2013 May-Jun;4(3):127-35
pubmed: 23584095
Immunity. 2006 Apr;24(4):393-403
pubmed: 16618598
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4102-7
pubmed: 12651944
Trends Immunol. 2020 Jan;41(1):46-60
pubmed: 31822368
Immunity. 1998 Dec;9(6):859-69
pubmed: 9881976
Mol Cell. 2015 Nov 19;60(4):611-25
pubmed: 26549683
J Mol Biol. 2017 Jun 30;429(13):1934-1945
pubmed: 27894815
Annu Rev Immunol. 1996;14:459-81
pubmed: 8717521
Nat Struct Mol Biol. 2020 Nov;27(11):1057-1068
pubmed: 32895554
EMBO Rep. 2021 Feb 3;22(2):e51184
pubmed: 33410591
J Exp Med. 2014 Oct 20;211(11):2297-306
pubmed: 25288395
Nat Immunol. 2003 May;4(5):452-6
pubmed: 12692548
Cell Rep. 2015 Sep 29;12(12):2086-98
pubmed: 26365193
Proc Natl Acad Sci U S A. 2021 Jul 20;118(29):
pubmed: 34253616
Phys Rev E Stat Nonlin Soft Matter Phys. 2015 Sep;92(3):032717
pubmed: 26465508
Nat Rev Immunol. 2016 Mar;16(3):164-76
pubmed: 26898111
Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11584-9
pubmed: 21709240
PLoS Biol. 2014 Apr 01;12(4):e1001831
pubmed: 24691034
Nature. 2019 Nov;575(7782):385-389
pubmed: 31666703
Annu Rev Immunol. 1989;7:537-59
pubmed: 2653375
EMBO J. 2013 Aug 28;32(17):2392-406
pubmed: 23921552
Cell. 2011 Feb 4;144(3):353-63
pubmed: 21255825
Cell Rep. 2020 Feb 18;30(7):2136-2149.e4
pubmed: 32075733
Trends Mol Med. 2006 Sep;12(9):432-9
pubmed: 16861038
J Immunol. 2004 Mar 15;172(6):3382-4
pubmed: 15004135
Cell. 2014 Dec 18;159(7):1524-37
pubmed: 25483777
DNA Repair (Amst). 2017 Jun;54:8-12
pubmed: 28388461
Blood. 2014 Jul 10;124(2):229-39
pubmed: 24850757
Cell Res. 2011 Mar;21(3):421-34
pubmed: 21263457
Cell Cycle. 2014;13(14):2153-4
pubmed: 24963723
J Exp Med. 2012 Jul 2;209(7):1379-89
pubmed: 22665573
Nat Rev Mol Cell Biol. 2018 Jul;19(7):464-478
pubmed: 29740129
Cell Rep. 2019 Dec 17;29(12):3902-3915.e8
pubmed: 31851922
Mol Cell. 2011 Dec 23;44(6):928-41
pubmed: 22195966
J Exp Med. 2013 Jul 1;210(7):1481-92
pubmed: 23752228
Nature. 2008 Feb 14;451(7180):841-5
pubmed: 18273020
J Exp Med. 2018 Mar 5;215(3):761-771
pubmed: 29374026
Cell. 2010 Oct 1;143(1):122-33
pubmed: 20887897
J Exp Med. 2012 Oct 22;209(11):2099-111
pubmed: 23008333
Mol Cell. 2014 Oct 23;56(2):298-310
pubmed: 25263594