Epigenomic Modifications Mediating Antibody Maturation

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.

Keywords: B cell maturation; antibody diversity; class-switch recombination; cytosine deamination; epigenetic modifications; epigenomics and epigenetics; somatic hypermutation.

Figure 1

Epigenomic modifications directing antibody-diversification processes somatic hypermutation (SHM) and CSR. Green core histones and associated modifications are involved in chromatin de-compaction and enable transcription through the immunoglobulin (Ig) locus. All factors above the locus are important for the generation of DSBs while everything below encourages mutagenic repair at the V region, and DSB repair at donor and acceptor S regions (Sμ and Sx, respectively). Blue histones and affiliated modifications help recruit or tether AID and other factors that facilitate production of DSBs. Purple DNA and RNA are linked with sequences and structures that facilitate AID recruitment or targeting. Red core histones and accessory modifications recruit DNA repair proteins to ensure excision of intervening C_H region for successful class switching as well as error-prone polymerases to the V region.

Figure 2

DNA damage repair pathways dictate class-switch recombination (CSR) efficiency. An overview of the histone modifications, and the writers and readers associated with them that are essential for CSR, as well as suggestions of additional likely factors. Color = confirmed in NHEJ and CSR, Gray = DNA damage repair factors not yet shown to affect CSR. The key proteins and histone modifications that have been shown to be essential for resolving the DNA double-strand breaks in CSR are summarized. A common theme is the recruitment of 53BP1, which is essential for efficient repair and isotype switching. Importantly, these repair pathways also function in NHEJ. Additional DNA damage repair proteins and histone modifications that have not yet been shown to play a role in CSR are indicated in gray. Some proteins and histone marks involved in other repair pathways, such as homologous recombination (HR), are also indicated in the figure. As these pathways inhibit the NHEJ pathways, they may provide negative control of CSR. Indeed, knockdown of BRCA1 has been shown to increase isotype switching efficiency.