The Chromatin Reader ZMYND8 Regulates Igh Enhancers to Promote Immunoglobulin Class Switch Recombination

Abstract

SummaryClass switch recombination (CSR) is a DNA recombination reaction that diversifies the effector component of antibody responses. CSR is initiated by activation-induced cytidine deaminase (AID), which targets transcriptionally active immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3′ Igh super-enhancer, 3′ regulatory region (3′RR), is essential for acceptor region transcription, but how this function is regulated is unknown. Here, we identify the chromatin reader ZMYND8 as an essential regulator of the 3′RR. In B cells, ZMYND8 binds promoters and super-enhancers, including the Igh enhancers. ZMYND8 controls the 3′RR activity by modulating the enhancer transcriptional status. In its absence, there is increased 3′RR polymerase loading and decreased acceptor region transcription and CSR. In addition to CSR, ZMYND8 deficiency impairs somatic hypermutation (SHM) of Igh, which is also dependent on the 3′RR. Thus, ZMYND8 controls Igh diversification in mature B lymphocytes by regulating the activity of the 3′ Igh super-enhancer.

Distinct Requirements of CHD4 during B Cell Development and Antibody Response

“…Whether both transcriptional and post-transcriptional activities of the NuRD complex contribute to regulate p53 levels in activated B cells is not clear at present, but both appear to be mediated via NuRD-dependent function of CHD4. In this regard, another NuRD complex associated factor ZMNYD8 has recently been shown to influence CSR by regulating the activity of the 3 ’ Igh super-enhancer ( Delgado-Benito et al, 2018 ). Additionally, on the basis of the ability of the NuRD complex to regulate acetylation of p53 protein, it is possible that it could also impact PTMs of AID and other factors that participate in different stages of B cell development and differentiation.…”

PDGFA-associated protein 1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification

“…Upon cytokine stimulation, CH12 cells express AID and undergo CSR to IgA with high efficiency (Nakamura et al, 1996). CRISPR-Cas9-mediated deletion of factors required for CSR reduces the efficiency of isotype switching in this cell line (Delgado-Benito et al, 2018). Among all tested candidates, targeting of Pdap1 resulted in a considerable reduction of CSR (Fig.…”

“…Selected clones R1/R2 and P1/3 were validated at the level of genomic scar and protein expression. The sequences of the gRNAs used in these studies (this paper; Delgado-Benito et al, 2018) are listed in Table S2.…”

Establishment and function of chromatin modification at enhancers

“…While initial studies identified mainly proteins whose recruitment to chromatin was mediated via interaction of PHD domains with H3K4me2 or H3K4me3 [107], there is evidence that certain PHD domains can also recognize lower-order methylation or even unmethylated lysines [108]. In fact, ZMYND8 has been identified as a PHD domain-containing chromatin factor at enhancers whose recruitment may be stabilized by the presence of unmethylated or monomethylated H3K4 [109][110][111]. Recent evidence suggests that H3K4me1 may also contribute to complex formation on chromatin through interaction with the PHD1-PHD2 domains of BAF45C, a member of the BAF chromatin remodelling complex [112].…”