H3K9 dimethyltransferase G9a is an important epigenetic modulator of B cell differentiation

Abstract

Plasma cell differentiation is a tightly regulated process coordinated by the timed expression of several transcription factors as well as histone modifying enzymes that modulate chromatin accessibility. During this process, the histone methyltransferase (HMT) G9a, dimethylates histone H3 lysine 9 (H3K9) at promoters and inhibits gene expression through the recruitment of proteins that impair chromatin accessibility. HMTs are expressed ubiquitously but display distinct enzymatic activities and patterns of chromosomal localization. During plasma cell differentiation, G9a was found to co-localize with Blimp-1, which is required to silence genes associated with a B cell fate and cellular proliferation. However, the processes that are modulated by G9a mediated dimethylation during plasma cell formation remain to be elucidated. To study the role of G9a in plasma cell differentiation, we crossed G9a fl/flmice onto the CD19 Cre/+background (G9aKO mice). Stimulation of CD19 Cre/+(CreCtrl) and G9aKO mice with the T cell independent antigen LPS resulted in a significant increase of activated B cells and plasmablast in G9aKO mice. Further characterization of this phenotype, identified a skewing of the mature B cell sub-populations in G9aKO mice, accompanied by altered proliferation rates when challenged. ATAC-Seq and RNA-Seq will be used to identify chromatin accessibility and expression changes in G9a deficient mice. The CUT&Tag assay will also be used to validate regions that are subject to direct modulation by G9a during plasma cell differentiation. Together, our data suggests that G9a contributes to regulating proliferation during plasma cell differentiation. his work is supported by grants from NIH/NIAID (RO1 AI123733 and P01 AI125180 to JMB)