Abstract
Epigenetic modifications, such as histone post-translational modifications, DNA methylation, and alteration of gene expression by non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are heritable changes that are independent from the genomic DNA sequence. These regulate gene activities and, therefore, cellular functions. Epigenetic modifications act in concert with transcription factors and play critical roles in B cell development and differentiation, thereby modulating antibody responses to foreign- and self-antigens. Upon antigen encounter by mature B cells in the periphery, alterations of these lymphocytes epigenetic landscape are induced by the same stimuli that drive the antibody response. Such alterations instruct B cells to undergo immunoglobulin (Ig) class switch DNA recombination (CSR) and somatic hypermutation (SHM), as well as differentiation to memory B cells or long-lived plasma cells for the immune memory. Inducible histone modifications, together with DNA methylation and miRNAs modulate the transcriptome, particularly the expression of activation-induced cytidine deaminase, which is essential for CSR and SHM, and factors central to plasma cell differentiation, such as B lymphocyte-induced maturation protein-1. These inducible B cell-intrinsic epigenetic marks guide the maturation of antibody responses. Combinatorial histone modifications also function as histone codes to target CSR and, possibly, SHM machinery to the Ig loci by recruiting specific adaptors that can stabilize CSR/SHM factors. In addition, lncRNAs, such as recently reported lncRNA-CSR and an lncRNA generated through transcription of the S region that form G-quadruplex structures, are also important for CSR targeting. Epigenetic dysregulation in B cells, including the aberrant expression of non-coding RNAs and alterations of histone modifications and DNA methylation, can result in aberrant antibody responses to foreign antigens, such as those on microbial pathogens, and generation of pathogenic autoantibodies, IgE in allergic reactions, as well as B cell neoplasia. Epigenetic marks would be attractive targets for new therapeutics for autoimmune and allergic diseases, and B cell malignancies.
Highlights
Epigenetic changes brought about by genetic susceptibility and/ or environmental exposure can modulate gene expression and alter cellular functions without altering genomic sequences [1]
By using well-characterized short-chain fatty acid (SCFA) HDIs, valproic acid (VPA) [116], and butyrate [117], we have shown that HDIs regulate intrinsic B cell functions that are critical in shaping effective antibody and autoantibody responses
Epigenetic changes are critical in shaping B cell differentiation functions, such as class switch DNA recombination (CSR), somatic hypermutation (SHM), generation of plasma cells as well as memory B cells, for the production of class-switched and high affinity antibodies
Summary
Epigenetic changes brought about by genetic susceptibility and/ or environmental exposure can modulate gene expression and alter cellular functions without altering genomic sequences [1]. In B cells, epigenetic marks, such as DNA methylation, histone modifications, and miRNAs, are induced by the same stimuli that drive the antibody response, and modulate the transcriptome, especially the expression of AID, which is essential for SHM and CSR, and factors critical for plasma cell differentiation, such as Blimp-1 [4]. It has been recently shown that histone acetyltransferase monocytic leukemia zinc finger protein (MOZ), which targets H3K9 and plays a role in stem cell selfrenewal, regulates B cell memory formation, controlling memory compartment composition [104] This activity of MOZ is B cellintrinsic and is required for establishing the germinal center gene expression program. Altered composition and decreased bacterial diversity of gut microbiota would lead to changes in absolute and relative levels of SCFA HDIs and, changes in systemic IgG, IgA and IgE levels and specificities, which contribute to altered immunity and increased susceptibility to immune-mediated diseases
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