Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/5101
Activation-induced cytidine deaminase targets SUV4-20-mediated histone H4K20 trimethylation to class-switch recombination sites
Rodriguez-Cortez, Virginia C. | Martinez-Redondo, Paloma | Catala-Moll, Francesc | Rodriguez-Ubreva, Javier | Garcia-Gomez, Antonio | Poorani-Subramani, Ganesh | Ciudad, Laura | Hernando, Henar | Perez-Garcia, Arantxa CNIC | Company, Carlos | Urquiza, Jose M. | Ramiro, Almudena R CNIC | Di Noia, Javier M. | Vaquero, Alejandro | Ballestar, Esteban
Sci Rep. 2017; 7(1):7594
Activation-induced cytidine deaminase (AID) triggers antibody diversification in B cells by catalysing deamination and subsequently mutating immunoglobulin (Ig) genes. Association of AID with RNA Pol II and occurrence of epigenetic changes during Ig gene diversification suggest participation of AID in epigenetic regulation. AID is mutated in hyper-IgM type 2 (HIGM2) syndrome. Here, we investigated the potential role of AID in the acquisition of epigenetic changes. We discovered that AID binding to the IgH locus promotes an increase in H4K20me3. In 293F cells, we demonstrate interaction between co-transfected AID and the three SUV4-20 histone H4K20 methyltransferases, and that SUV4-20H1.2, bound to the IgH switch (S) mu site, is replaced by SUV4-20H2 upon AID binding. Analysis of HIGM2 mutants shows that the AID truncated form W68X is impaired to interact with SUV4-20H1.2 and SUV4-20H2 and is unable to bind and target H4K20me3 to the Smu site. We finally show in mouse primary B cells undergoing class-switch recombination (CSR) that AID deficiency associates with decreased H4K20me3 levels at the Smu site. Our results provide a novel link between SUV4-20 enzymes and CSR and offer a new aspect of the interplay between AID and histone modifications in setting the epigenetic status of CSR sites.
DOUBLE-STRAND BREAKS | SOMATIC HYPERMUTATION | SUPER-ENHANCERS | RECRUIT AID | B-CELLS | DNA | METHYLATION | REGIONS | DEMETHYLATION | REPAIR