Functional role of the histone demethylase UTX in B cell development and antibody responses in vivo

H3K27 trimethylation, catalyzed by the Polycomb Repressive Complex 2 (PRC2), is mainly associated with transcriptional repression of target genes. PRC2 activity is counterbalanced by UTX and JMJD3, belonging to the family of Jmj-C-containing H3K27me3 demethylases. UTX acts in concert with members of the Mixed Lineage Leukemia (MLL) family of H3K4 methyltransferases to sustain gene transcription. In vivo studies have assigned to UTX important roles in hematopoiesis, particularly in immune cell differentiation. We showed that Utx is expressed throughout B cell development. To study the role of UTX in B lymphopoiesis, we crossed Utx conditional knock-out mice to the Mb1cre/+ strain, to inactivate the demethylase throughout B cell development, starting from pro-B cells. Our results suggest that UTX influences B cell physiology in multiple ways, controlling mature B cell subset differentiation and survival, B cell distribution among lymphoid organs, Ig isotype switching and antigen-driven germinal center (GC) B cell clonal selection. As a result of these defects, B cell-specific Utx deficiency causes a mild humoral immunodeficiency, affecting primarily intestinal IgA-linked immunity. Importantly, these defects resemble those described in patients affected by the Kabuki Syndrome, a genetic disorder caused by mutations in either UTX or in the MLL methyltransferase KMT2D. Chromatin immunoprecipitation studies coupled to sequencing performed on Utx mutant resting and GC B cells started to unveil the identity of the transcriptional and epigenetic networks under the influence of UTX. These studies could improve our understanding of how deregulated UTX participates to the pathogenesis of immunological disorders, including B cell malignancies.