Epigenomic modifications mediating antibody maturation

This is the final version of the article. Available from the publisher via the DOI in this record.Epigenetic modifications, such as histone modifications, DNA methylation status, and non-coding RNAs (ncRNA), all contribute to antibody maturation during somatic hypermutation (SHM) and class-switch recombination (CSR). Histone modifications alter the chromatin landscape and, together with DNA primary and tertiary structures, they help recruit Activation-Induced Cytidine Deaminase (AID) to the immunoglobulin (Ig) locus. AID is a potent DNA mutator, which catalyzes cytosine-to-uracil deamination on single-stranded DNA to create U:G mismatches. It has been shown that alternate chromatin modifications, in concert with ncRNAs and potentially DNA methylation, regulate AID recruitment and stabilize DNA repair factors. We, hereby, assess the combination of these distinct modifications and discuss how they contribute to initiating differential DNA repair pathways at the Ig locus, which ultimately leads to enhanced antibody-antigen binding affinity (SHM) or antibody isotype switching (CSR). We will also highlight how misregulation of epigenomic regulation during DNA repair can compromise antibody development and lead to a number of immunological syndromes and cancer.The authors wish to thank Matthew Scharff, Shanzhi Wang, Sergio Roa, and Emma Knight for their insight, and funding for RC from the Biotechnology and Biological Research Council [BB/N017773/1], Royal Society [IE150290], and Academy of Medical Sciences Springboard Award. ECS and RBM are funded by Ph.D. studentships from the Biotechnology and Biological Research Council-funded South West Doctoral Training Partnership [BB/J014400/1] and the Engineering and Physical Sciences Research Council-funded Doctoral Training Partnership [EP/M506527/1], respectively