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

MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
2
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
3
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
4
Biochemistry Department, University Stuttgart, Stuttgart, Germany.
5
Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
6
Department of Physiology, Center of Physiology and Pharmacology & Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
7
Regensburg Center for Interventional Immunology (RCI), University Regensburg and University Medical Center, Regensburg, Germany.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
9
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria.
10
Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany.
11
Institute of Structural Biology, Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
12
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
13
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
14
Max Planck Institute for Informatics, Saarbrücken, Germany.
15
Medical University of Vienna, Vienna BioCenter (VBC), Vienna, Austria.
16
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. skubicek@cemm.oeaw.ac.at.
17
Department of Physiology, Center of Physiology and Pharmacology & Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. skubicek@cemm.oeaw.ac.at.

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.

PMID:
31133746
DOI:
10.1038/s41588-019-0413-z
[Indexed for MEDLINE]

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