MTHFD1 Interaction With BRD4 Links Folate Metabolism to Transcriptional Regulation

Nat Genet. 2019 Jun;51(6):990-998. doi: 10.1038/s41588-019-0413-z. Epub 2019 May 27.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Chromatin / genetics
  • Folic Acid / metabolism*
  • Gene Expression Regulation*
  • Gene Knockout Techniques
  • Humans
  • Loss of Function Mutation
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / metabolism*
  • Minor Histocompatibility Antigens / metabolism*
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Interaction Maps
  • Protein Transport
  • Signal Transduction
  • Transcription Factors / metabolism*
  • Transcription, Genetic

Substances

  • BRD4 protein, human
  • Cell Cycle Proteins
  • Chromatin
  • Minor Histocompatibility Antigens
  • Nuclear Proteins
  • Transcription Factors
  • Folic Acid
  • MTHFD1 protein, human
  • Methylenetetrahydrofolate Dehydrogenase (NADP)