The histone acetyl reader bromodomain-containing protein 4 (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 genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1 (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1). 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; pharmacological 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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952269PMC
http://dx.doi.org/10.1038/s41588-019-0413-zDOI Listing

Publication Analysis

Top Keywords

interaction brd4
8
gene expression
8
mthfd1
5
brd4
5
mthfd1 interaction
4
brd4 links
4
links folate
4
folate metabolism
4
metabolism transcriptional
4
transcriptional regulation
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!