MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation

Autor: Jung-Ming G. Lin, Christian Schmidl, Hans Michael Maric, Emilio Casanova, Keiryn L. Bennett, Gerald Hofstaetter, André C. Müller, Johannes Zuber, Robert Kralovics, Anna Ringler, Katja Parapatics, Freya Klepsch, Wanhui You, Karl Mechtler, Matthias Farlik, Jörg Menche, André F. Rendeiro, Stefan Kubicek, Sandra Schick, Bettina Guertl, Sara Sdelci, Kristaps Klavins, Michael Schuster, Herwig P. Moll, Christoph Bock, Thomas Penz, Philipp Rathert, Otto Hudecz, James E. Bradner, Georg E. Winter, Shuang-Yan Wang, Fiorella Schischlik, Peter Májek, Pisanu Buphamalai, Matthew Oldach, Richard Imre, Dennis L. Buckley
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Formyltetrahydrofolate synthetase
Transcription
Genetic
Cell Cycle Proteins
Article
Minor Histocompatibility Antigens
03 medical and health sciences
Gene Knockout Techniques
0302 clinical medicine
Folic Acid
Loss of Function Mutation
Cell Line
Tumor
Gene expression
Protein Interaction Mapping
Genetics
Transcriptional regulation
Humans
Epigenetics
Protein Interaction Maps
education
030304 developmental biology
Regulation of gene expression
Cell Nucleus
Methylenetetrahydrofolate Dehydrogenase (NADP)
0303 health sciences
education.field_of_study
biology
Nuclear Proteins
Chromatin
3. Good health
Cell biology
Protein Transport
Histone
Gene Expression Regulation
Methylenetetrahydrofolate dehydrogenase
biology.protein
030217 neurology & neurosurgery
Protein Binding
Signal Transduction
Transcription Factors
Zdroj: Nature genetics
Nature Genetics
ISSN: 1546-1718
1061-4036
Popis: 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.
Databáze: OpenAIRE
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