Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction
Por:
Catala-Moll, F, Ferrete-Bonastre, AG, Li, TL, Weichenhan, D, Lutsik, P, Ciudad, L, Alvarez-Prado, AF, Rodriguez-Ubreva, J, Klemann, C, Speckmann, C, Vilas-Zornoza, A, Abolhassani, H, Martinez-Gallo, M, Dieli-Crimi, R, Riviere, JG, Martin-Nalda, A, Colobran, R, Soler-Palacin, P, Kracker, S, Hammarstrom, L, Prosper, F, Durandy, A, Grimbacher, B, Plass, C and Ballestar, E
Publicada:
21 may 2021
Ahead of Print:
1 may 2021
Resumen:
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 naive and memory B cells both display widespread DNA methylation alterations, of which similar to 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 naive 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.
Filiaciones:
Catala-Moll, F:
Josep Carreras Res Inst IJC, Epigenet & Immune Dis Grp, Badalona 08916, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Programme PEBC, Chromatin & Dis Grp, Barcelona 08908, Spain
:
Josep Carreras Res Inst IJC, Epigenet & Immune Dis Grp, Badalona 08916, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Programme PEBC, Chromatin & Dis Grp, Barcelona 08908, Spain
:
Josep Carreras Res Inst IJC, Epigenet & Immune Dis Grp, Badalona 08916, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Programme PEBC, Chromatin & Dis Grp, Barcelona 08908, Spain
Weichenhan, D:
German Canc Res Ctr, Div Canc Epigen, D-69120 Heidelberg, Germany
Lutsik, P:
German Canc Res Ctr, Div Canc Epigen, D-69120 Heidelberg, Germany
Ciudad, L:
Josep Carreras Res Inst IJC, Epigenet & Immune Dis Grp, Badalona 08916, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Programme PEBC, Chromatin & Dis Grp, Barcelona 08908, Spain
Alvarez-Prado, AF:
Ctr Nacl Invest Cardiovasc Carlos III CNIC, B Cell Biol Lab, Madrid 28029, Spain
:
Josep Carreras Res Inst IJC, Epigenet & Immune Dis Grp, Badalona 08916, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Programme PEBC, Chromatin & Dis Grp, Barcelona 08908, Spain
Klemann, C:
Univ Freiburg, Fac Med, Ctr Chron Immunodeficiency CCI, Med Ctr,Inst Immunodeficiency, D-79110 Freiburg, Germany
Hannover Med Sch, Dept Paediat Pulmonol Allergy & Neonatol, Hannover, Germany
Speckmann, C:
Univ Freiburg, Fac Med, Ctr Chron Immunodeficiency CCI, Med Ctr,Inst Immunodeficiency, D-79110 Freiburg, Germany
Univ Freiburg, Fac Med, Ctr Pediat & Adolescent Med, Med Ctr, Freiburg, Germany
Vilas-Zornoza, A:
Univ Navarra, Ctr Appl Med Res CIMA, Pamplona 31008, Spain
Abolhassani, H:
Karolinska Inst, Karolinska Univ Hosp Huddinge, Dept Lab Med, Div Clin Immunol, SE-14186 Stockholm, Sweden
Martinez-Gallo, M:
Hosp Univ Vall dHebron, Immunol Div, Barcelona, Spain
Vall dHebron Res Inst VHIR, Diagnost Immunol Res Grp, Barcelona, Spain
Dieli-Crimi, R:
Hosp Univ Vall dHebron, Immunol Div, Barcelona, Spain
Vall dHebron Res Inst VHIR, Diagnost Immunol Res Grp, Barcelona, Spain
Riviere, JG:
Autonomous Univ Barcelona, Hosp Univ Vall dHebron, Vall dHebron Res Inst VHIR, Pediat Infect Dis & Immunodeficiencies Unit, Barcelona, Spain
Hosp Univ Vall dHebron, Vall dHebron Inst Recerca VHIR, Infect Immunocompromised Pediat Patients Res Grp, Barcelona 08035, Spain
Jeffrey Modell Diagnost & Res Ctr Primary Immunod, Barcelona, Spain
Martin-Nalda, A:
Autonomous Univ Barcelona, Hosp Univ Vall dHebron, Vall dHebron Res Inst VHIR, Pediat Infect Dis & Immunodeficiencies Unit, Barcelona, Spain
Hosp Univ Vall dHebron, Vall dHebron Inst Recerca VHIR, Infect Immunocompromised Pediat Patients Res Grp, Barcelona 08035, Spain
Jeffrey Modell Diagnost & Res Ctr Primary Immunod, Barcelona, Spain
Colobran, R:
Hosp Univ Vall dHebron, Immunol Div, Barcelona, Spain
Vall dHebron Res Inst VHIR, Diagnost Immunol Res Grp, Barcelona, Spain
Jeffrey Modell Diagnost & Res Ctr Primary Immunod, Barcelona, Spain
Univ Autonoma Barcelona UAB, Dept Cell Biol Physiol & Immunol, Bellaterra, Catalonia, Spain
Soler-Palacin, P:
Autonomous Univ Barcelona, Hosp Univ Vall dHebron, Vall dHebron Res Inst VHIR, Pediat Infect Dis & Immunodeficiencies Unit, Barcelona, Spain
Hosp Univ Vall dHebron, Vall dHebron Inst Recerca VHIR, Infect Immunocompromised Pediat Patients Res Grp, Barcelona 08035, Spain
Jeffrey Modell Diagnost & Res Ctr Primary Immunod, Barcelona, Spain
Kracker, S:
Univ Paris, Imagine Inst, Lab Human Lymphohematopoiesis, INSERM,UMR 1163, Paris, France
Hammarstrom, L:
Karolinska Inst, Karolinska Univ Hosp Huddinge, Dept Lab Med, Div Clin Immunol, SE-14186 Stockholm, Sweden
Prosper, F:
Univ Navarra, Ctr Appl Med Res CIMA, Pamplona 31008, Spain
Durandy, A:
Univ Paris, Imagine Inst, Lab Human Lymphohematopoiesis, INSERM,UMR 1163, Paris, France
Grimbacher, B:
Univ Freiburg, Fac Med, Ctr Chron Immunodeficiency CCI, Med Ctr,Inst Immunodeficiency, D-79110 Freiburg, Germany
German Ctr Infect Res DZIF, Satellite Ctr Freiburg, Freiburg, Germany
Albert Ludwigs Univ, Ctr Integrat Biol Signalling Studies CIBSS, Freiburg, Germany
Hannover Med Sch, Cluster Excellence 2155, RESIST, Satellite Ctr Freiburg, Hannover, Germany
UCL, Royal Free Hosp, Inst Immun & Transplantat, London, England
Plass, C:
German Canc Res Ctr, Div Canc Epigen, D-69120 Heidelberg, Germany
:
Josep Carreras Res Inst IJC, Epigenet & Immune Dis Grp, Badalona 08916, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Programme PEBC, Chromatin & Dis Grp, Barcelona 08908, Spain
Green Published, Green Submitted, gold
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