Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Activation-induced deaminase (AID) initiates antibody diversification in germinal center B cells by deaminating cytosines, leading to somatic hypermutation and class-switch recombination. Loss-of-function mutations in AID lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody defic...

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Autores: Català Moll, Francesc, Ferreté Bonastre, Anna Guiomar, Li, Tianlu, Weichenhan, Dieter, Lutsik, Pavlo, Ciudad, Laura, Álvarez Prado, Ángel F., Rodríguez Ubreva, Javier, Klemann, Christian, Speckmann, Carsten, Vilas Zornoza, Amaya, Abolhassani, Hassan, Martínez Gallo, Mónica, Dieli Crimi, Romina, Rivière, Jacques G., Martín Nalda, Andrea, Colobran, Roger, Soler Palacín, Pere, Kracker, Sven, Hammarström, Lennart, Prosper, Felipe, Durandy, Anne, Grimbacher, Bodo, Plass, Christoph, Ballestar Tarín, Esteban
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/178643
Acceso en línea:https://hdl.handle.net/2445/178643
Access Level:acceso abierto
Palabra clave:ADN
Metilació
Cèl·lules B
DNA
Methylation
B cells
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spelling Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reactionCatalà Moll, FrancescFerreté Bonastre, Anna GuiomarLi, TianluWeichenhan, DieterLutsik, PavloCiudad, LauraÁlvarez Prado, Ángel F.Rodríguez Ubreva, JavierKlemann, ChristianSpeckmann, CarstenVilas Zornoza, AmayaAbolhassani, HassanMartínez Gallo, MónicaDieli Crimi, RominaRivière, Jacques G.Martín Nalda, AndreaColobran, RogerSoler Palacín, PereKracker, SvenHammarström, LennartProsper, FelipeDurandy, AnneGrimbacher, BodoPlass, ChristophBallestar Tarín, EstebanADNMetilacióCèl·lules BDNAMethylationB cellsActivation-induced deaminase (AID) initiates antibody diversification in germinal center B cells by deaminating cytosines, leading to somatic hypermutation and class-switch recombination. Loss-of-function mutations in AID lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated deamination has been proposed as leading to active demethylation of 5-methycytosines in the DNA, although evidence both supports and casts doubt on such a role. In this study, using whole-genome bisulfite sequencing of HIGM2 B cells, we investigated direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation alterations, of which ∼25% are attributable to active DNA demethylation. For genes that undergo active demethylation that is impaired in HIGM2 individuals, our analysis indicates that AID is not directly involved. We demonstrate that the widespread alterations in the DNA methylation and expression profiles of HIGM2 naïve B cells result from premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data support a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.Oxford University Press2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/178643Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1093/nar/gkab322Nucleic Acids Research, 2021, vol. 49, num. 9, p. 5057-5073https://doi.org/10.1093/nar/gkab322cc by-nc (c) Català Moll et al., 2021http://creativecommons.org/licenses/by-nc/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1786432026-05-27T06:46:51Z
dc.title.none.fl_str_mv Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction
title Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction
spellingShingle Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction
Català Moll, Francesc
ADN
Metilació
Cèl·lules B
DNA
Methylation
B cells
title_short Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction
title_full Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction
title_fullStr Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction
title_full_unstemmed Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction
title_sort Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction
dc.creator.none.fl_str_mv Català Moll, Francesc
Ferreté Bonastre, Anna Guiomar
Li, Tianlu
Weichenhan, Dieter
Lutsik, Pavlo
Ciudad, Laura
Álvarez Prado, Ángel F.
Rodríguez Ubreva, Javier
Klemann, Christian
Speckmann, Carsten
Vilas Zornoza, Amaya
Abolhassani, Hassan
Martínez Gallo, Mónica
Dieli Crimi, Romina
Rivière, Jacques G.
Martín Nalda, Andrea
Colobran, Roger
Soler Palacín, Pere
Kracker, Sven
Hammarström, Lennart
Prosper, Felipe
Durandy, Anne
Grimbacher, Bodo
Plass, Christoph
Ballestar Tarín, Esteban
author Català Moll, Francesc
author_facet Català Moll, Francesc
Ferreté Bonastre, Anna Guiomar
Li, Tianlu
Weichenhan, Dieter
Lutsik, Pavlo
Ciudad, Laura
Álvarez Prado, Ángel F.
Rodríguez Ubreva, Javier
Klemann, Christian
Speckmann, Carsten
Vilas Zornoza, Amaya
Abolhassani, Hassan
Martínez Gallo, Mónica
Dieli Crimi, Romina
Rivière, Jacques G.
Martín Nalda, Andrea
Colobran, Roger
Soler Palacín, Pere
Kracker, Sven
Hammarström, Lennart
Prosper, Felipe
Durandy, Anne
Grimbacher, Bodo
Plass, Christoph
Ballestar Tarín, Esteban
author_role author
author2 Ferreté Bonastre, Anna Guiomar
Li, Tianlu
Weichenhan, Dieter
Lutsik, Pavlo
Ciudad, Laura
Álvarez Prado, Ángel F.
Rodríguez Ubreva, Javier
Klemann, Christian
Speckmann, Carsten
Vilas Zornoza, Amaya
Abolhassani, Hassan
Martínez Gallo, Mónica
Dieli Crimi, Romina
Rivière, Jacques G.
Martín Nalda, Andrea
Colobran, Roger
Soler Palacín, Pere
Kracker, Sven
Hammarström, Lennart
Prosper, Felipe
Durandy, Anne
Grimbacher, Bodo
Plass, Christoph
Ballestar Tarín, Esteban
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ADN
Metilació
Cèl·lules B
DNA
Methylation
B cells
topic ADN
Metilació
Cèl·lules B
DNA
Methylation
B cells
description Activation-induced deaminase (AID) initiates antibody diversification in germinal center B cells by deaminating cytosines, leading to somatic hypermutation and class-switch recombination. Loss-of-function mutations in AID lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated deamination has been proposed as leading to active demethylation of 5-methycytosines in the DNA, although evidence both supports and casts doubt on such a role. In this study, using whole-genome bisulfite sequencing of HIGM2 B cells, we investigated direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation alterations, of which ∼25% are attributable to active DNA demethylation. For genes that undergo active demethylation that is impaired in HIGM2 individuals, our analysis indicates that AID is not directly involved. We demonstrate that the widespread alterations in the DNA methylation and expression profiles of HIGM2 naïve B cells result from premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data support a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/178643
url https://hdl.handle.net/2445/178643
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1093/nar/gkab322
Nucleic Acids Research, 2021, vol. 49, num. 9, p. 5057-5073
https://doi.org/10.1093/nar/gkab322
dc.rights.none.fl_str_mv cc by-nc (c) Català Moll et al., 2021
http://creativecommons.org/licenses/by-nc/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc (c) Català Moll et al., 2021
http://creativecommons.org/licenses/by-nc/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869403644213854208
score 15.300719

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