Selective modulation of B cell mRNA and microRNA expression by histone deacetylase inhibitor (IRM10P.615)

Abstract

As we suggested, epigenetic factors such as miRNAs, can interact with genetic programs to regulate B cell functions and inform antibody response. We have shown that histone deacetylase inhibitors (HDIs) valproic acid and butyrate, inhibited class-switch DNA recombination (CSR), somatic hypermutation (SHM) and plasma cell differentiation by modulating B cell intrinsic mechanisms. They repressed AID and Blimp-1 expression, which are critical for CSR/SHM and plasma cell differentiation, in mouse and human B cells by upregulating selected miRNAs that silenced AICDA/Aicda and PRDM1/Prdm-1 mRNAs, as demonstrated by qRT-PCRs. To further define the selectivity of HDI-mediated modulation of miRNA and gene expression, we performed miRNA-Seq and mRNA-Seq analysis in B cells stimulated with LPS plus IL-4 followed by VPA treatment. Consistent with our recent findings (J. Immunol. 193:5933-5950, 2014), these B cells showed reduced Aicda and Prdm1 expression, 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,. The HDI-mediated modulation of mRNA was very selective. Among over 22,000 mRNAs analyzed, less than 20 mRNAs, including Aicda and Prdm1, significantly expressed in activated B cells were reduced by over two fold. Our findings indicate that, in B cells, HDI selectively modulate mRNAs, possibly through miRNA upregulation and as a result of HDACs existing in unique contexts of HDAC/co-factor complexes,.