Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
21 05 2021
21 05 2021
Historique:
accepted:
19
04
2021
revised:
15
04
2021
received:
07
02
2020
pubmed:
6
5
2021
medline:
7
7
2021
entrez:
5
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33950194
pii: 6266447
doi: 10.1093/nar/gkab322
pmc: PMC8136777
doi:
Substances chimiques
Receptors, Antigen, B-Cell
0
AICDA (activation-induced cytidine deaminase)
EC 3.5.4.-
Cytidine Deaminase
EC 3.5.4.5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5057-5073Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
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