MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation.
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
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
18
04
2018
accepted:
04
04
2019
pubmed:
28
5
2019
medline:
10
7
2019
entrez:
29
5
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31133746
doi: 10.1038/s41588-019-0413-z
pii: 10.1038/s41588-019-0413-z
pmc: PMC6952269
mid: EMS82532
doi:
Substances chimiques
BRD4 protein, human
0
Cell Cycle Proteins
0
Chromatin
0
Minor Histocompatibility Antigens
0
Nuclear Proteins
0
Transcription Factors
0
Folic Acid
935E97BOY8
MTHFD1 protein, human
EC 1.5.1.5
Methylenetetrahydrofolate Dehydrogenase (NADP)
EC 1.5.1.5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
990-998Subventions
Organisme : European Research Council
ID : 772437
Pays : International
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