MTHFD1 links folate metabolism to BRD4-mediated transcriptional regulation

The histone acetyl-reader BRD4 is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for functional regulators and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1. We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression, and pharmacologic inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin-associated suggests a direct role for nuclear metabolism in the control of gene expression. 35 ChIP-seq samples for BRD4, MTHFD1 and H3K27ac were produced, along with the respective IgG controls in HAP1 cells treated with dBET6 or DMSO. 93 RNA-seq samples for WT, MTHFD1KO or treated cell were produced.