Abstract
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.
Highlights
Reviewed by: David Jonathan Fear, King’s College London, United Kingdom Anne Corcoran, Babraham Institute (BBSRC), United Kingdom
Epigenetic modifications, such as histone modifications, DNA methylation status, and non-coding RNAs, all contribute to antibody maturation during somatic hypermutation (SHM) and class-switch recombination (CSR)
Both SHM and CSR are initiated by the mutator protein, Activation-Induced Cytidine Deaminase (AID), which catalyzes cytosine-to-uracil deaminations on single-stranded DNA at Ig genes, to create U:G mismatches, which leads to immune diversity [1]
Summary
B cells experience dramatic fluctuations in their epigenomic landscape throughout hematopoiesis. It has become increasingly apparent that epigenetic modifications are indispensable for the antibody maturation processes during SHM and CSR at antibody producing genes Both SHM and CSR are initiated by the mutator protein, Activation-Induced Cytidine Deaminase (AID), which catalyzes cytosine-to-uracil deaminations on single-stranded DNA (ssDNA) at Ig genes, to create U:G mismatches, which leads to immune diversity [1]. Epigenomic Modifications Affecting Antibody Maturation processing of this regulated DNA damage, by DNA repair mechanisms, which forms the highly mutated antibody-binding variable (V) regions in SHM This gives rise to BCRs of differing affinities. We aim to provide a cohesive understanding of higher-order epigenomic processes critical for the regulation of B cell maturation, manipulation of DNA repair mechanisms, and insights into the development of debilitating cancer- and immune-based diseases
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