XLID syndrome gene Med12 promotes Ig isotype switching through chromatin modification and enhancer RNA regulation

Abstract

The transcriptional coactivator Med12 regulates gene expression through its kinase module. Here, we show a kinase module–independent function of Med12 in CSR. Med12 is essential for super-enhancer activation by collaborating with p300-Jmjd6/Carm1 coactivator complexes. Med12 loss decreases H3K27 acetylation and eRNA transcription with concomitant impairment of AID-induced DNA breaks, S-S synapse formation, and 3′RR-Eμ interaction. CRISPR-dCas9–mediated enhancer activation reestablishes the epigenomic and transcriptional hallmarks of the super-enhancer and fully restores the Med12 depletion defects. Moreover, 3′RR-derived eRNAs are critical for promoting S region epigenetic regulation, synapse formation, and recruitment of Med12 and AID to the IgH locus. We find that XLID syndrome–associated Med12 mutations are defective in both 3′RR eRNA transcription and CSR, suggesting that B and neuronal cells may have cell-specific super-enhancer dysfunctions. We conclude that Med12 is essential for IgH 3′RR activation/eRNA transcription and plays a central role in AID-induced antibody gene diversification and genomic instability in B cells.