Abstract
As we have suggested, epigenetic factors, such as microRNAs (miRNAs), can interact with genetic programs to regulate B cell functions, thereby informing antibody and autoantibody responses. We have shown that histone deacetylase (HDAC) inhibitors (HDI) inhibit the differentiation events critical to the maturation of the antibody response: class-switch DNA recombination (CSR), somatic hypermutation (SHM), and plasma cell differentiation, by modulating intrinsic B cell mechanisms. HDI repress the expression of AID and Blimp-1, which are critical for CSR/SHM and plasma cell differentiation, respectively, in mouse and human B cells by upregulating selected miRNAs that silenced AICDA/Aicda and PRDM1/Prdm1 mRNAs, as demonstrated by multiple qRT-PCRs (J Immunol 193:5933–5950, 2014). To further define the selectivity of HDI-mediated modulation of miRNA and gene expression, we performed genome-wide miRNA-Seq and mRNA-Seq analysis in B cells stimulated by LPS plus IL-4 and treated with HDI or nil. Consistent with what we have shown using qRT-PCR, these HDI-treated B cells displayed reduced expression of Aicda and Prdm1, and increased expression of miR-155, miR-181b, and miR-361, which target Aicda, and miR-23b, miR-30a, and miR-125b, which target Prdm1. In B cells induced to undergo CSR and plasma cell differentiation, about 23% of over 22,000 mRNAs analyzed were expressed at a significantly high copy number (more than 20 copies/cell). Only 18 (0.36%) of these highly expressed mRNAs, including Aicda, Prdm1, and Xbp1, were downregulated by HDI by 50% or more. Further, only 16 (0.30%) of the highly expressed mRNAs were upregulated (more than twofold) by HDI. The selectivity of HDI-mediated modulation of gene expression was emphasized by unchanged expression of the genes that are involved in regulation, targeting, or DNA repair processes of CSR, as well as unchanged expression of the genes encoding epigenetic regulators and factors that are important for cell signaling or apoptosis. Our findings indicate that, in B cells induced to undergo CSR and plasma cell differentiation, HDI modulate selected miRNAs and mRNAs, possibly as a result of HDACs existing in unique contexts of HDAC/cofactor complexes, as occurring in B lymphocytes, particularly when in an activated state.
Highlights
Epigenetic markers or factors, such as DNA methylation, histone posttranslational modifications, and microRNAs, dynamically regulate gene activities
We have shown that HDAC inhibitors (HDI) repress the expression of AID and Blimp-1, which are critical for class-switch DNA recombination (CSR)/somatic hypermutation (SHM) and plasma cell differentiation, respectively, in mouse and human B cells by upregulating selected miRNAs that silenced AICDA/Aicda and PRDM1/Prdm1 mRNAs, as demonstrated by multiple Quantitative RT-PCR (qRT-PCR) [16]
We have recently shown that HDI downregulated the expression of AID and Blimp-1 by upregulating miR-155, miR-181b, and miR-361, which silence Aicda mRNA, and miR-23b, miR-30a, and miR-125b, which silence Prdm1 mRNA, but not miR-19a/b, miR-20a, and miR-25, which are not known to regulate Aicda, Prdm1, or Xbp1 [16]
Summary
Epigenetic markers or factors, such as DNA methylation, histone posttranslational modifications, and microRNAs (miRNAs), dynamically regulate gene activities. Class-switched and hypermutated B cells further differentiate into antibody-secreting plasma cells in a fashion critically dependent on B lymphocyte-induced maturation protein 1 (Blimp, encoded by PRDM1 in human beings and Prdm in mice) [3], or transition to long-lived memory B cells, which can differentiate into plasma cells upon reactivation by antigen to mediate an anamnestic response [4]. Pathogenic autoantibodies, including those to nuclear components in systemic lupus erythematosus (SLE) patients [5, 6], are classswitched and hypermutated [7, 8]. Epigenetic dysregulation of B cells can result in aberrant antibody responses to exogenous antigens, such as those on viruses and bacteria, or self-antigens, such as chromatin, histones, and dsDNA in lupus [1, 7]
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