Epigenetic Codes Programing Class Switch Recombination

Abstract

Class switch recombination imparts B cells with a fitness-associated adaptive -advantage during a humoral immune response by using a precision-tailored DNA excision and ligation process to swap the default constant region gene of the antibody with a new one that has unique effector functions. This secondary diversification of the antibody repertoire is a hallmark of the adaptability of B cells when confronted with environmental and pathogenic challenges. Given that the nucleotide sequence of genes during class switching remains unchanged (genetic constraints), it is logical and necessary therefore, to integrate the adaptability of B cells to an epigenetic state, which is dynamic and can be heritably modulated before, after, or even during an antibody-dependent immune response. Epigenetic regulation encompasses heritable changes that affect function (phenotype) without altering the sequence information embedded in a gene, and include histone, DNA and RNA modifications. Here, we review current literature on how B cells use an epigenetic code language as a means to ensure antibody plasticity in light of pathogenic insults.

Keywords: AID; DNA deamination; DNA repair; non-coding RNAs; recombination.

Figure 1

Overview of CSR. Each of the CH genes is preceded by transcribed, repetitive DNA elements called switch (S) regions. AID mediated DNA deamination, followed by processing of deaminated cytidines by components of the base excision and mismatch repair machineries (UNG and Msh2, respectively) lead to the generation of DNA double-strand breaks. End-joining of ­double-strand breaks between donor and acceptor S regions completes CSR. Scheme for CSR to IgE is shown; block curved arrows indicate germline transcription from promoters upstream of Sμ and Sε; *represents a putative, but uncharacterized switch region upstream of Cδ.

Figure 2

The histone modifications on donor and acceptor S regions in naïve and activated B cells are shown.

Figure 3

Regulatory clusters containing super-enhancers modulate AID mistargeting. Convergent transcription between promoters of target gene and super-enhancers from topologically associated domains (TAD) allow access of AID to single-stranded DNA and promote off-target activity. DHS – Dnase1 hypersensitive sites.

Figure 4

Post-splicing RNA-dependent targeting mechanism of AID during CSR. Transcribed S region are spliced, debranched (by DBR1) and the switch RNA assumes G-quadruplex conformation that allows structure- and sequence-dependent AID targeting back to S region DNA