Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting

0559752 - ÚMG 2023 RIV DE eng J - Článek v odborném periodiku
Dinesh, R. K. - Barnhill, B. - Ilanges, A. - Wu, L. - Michelson, D.A. - Šenigl, Filip - Alinikula, J. - Shabanowitz, J. - Hunt, D. F. - Schatz, D. G.
Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting.
European Journal of Immunology. Roč. 50, č. 3 (2020), s. 380-395. ISSN 0014-2980. E-ISSN 1521-4141
Grant CEP: GA ČR GA15-24776S
Institucionální podpora: RVO:68378050
Klíčová slova: aid * e2a * mef2b * Ramos B cell line * Somatic hypermutation
Obor OECD: Immunology
Impakt faktor: 5.532, rok: 2020
Způsob publikování: Open access
https://onlinelibrary.wiley.com/doi/10.1002/eji.201948357

Secondary diversification of the Ig repertoire occurs through somatic hypermutation (SHM), gene conversion (GCV), and class switch recombination (CSR)-three processes that are initiated by activation-induced cytidine deaminase (AID). AID targets Ig genes at orders of magnitude higher than the rest of the genome, but the basis for this specificity is poorly understood. We have previously demonstrated that enhancers and enhancer-like sequences from Ig genes are capable of stimulating SHM of neighboring genes in a capacity distinct from their roles in increasing transcription. Here, we use an in vitro proteomics approach to identify E-box, MEF2, Ets, and Ikaros transcription factor family members as potential binders of these enhancers. ChIP assays in the hypermutating Ramos B cell line confirmed that many of these factors bound the endogenous Ig lambda enhancer and/or the IgH intronic enhancer (E mu) in vivo. Further investigation using SHM reporter assays identified binding sites for E2A and MEF2B in E mu and demonstrated an association between loss of factor binding and decreases in the SHM stimulating activity of E mu mutants. Our results provide novel insights into trans-acting factors that dictate SHM targeting and link their activity to specific DNA binding sites within Ig enhancers.
Trvalý link: https://hdl.handle.net/11104/0332957