Sdelci, Sara and Rendeiro, Andre F. and Rathert, Philipp and You, Wanhui and Lin, Jung-Ming G. and Ringler, Anna and Hofstaetter, Gerald and Moll, Herwig P. and Guertl, Bettina and Farlik, Matthias and Schick, Sandra and Klepsch, Freya and Oldach, Matthew and Buphamalai, Pisanu and Schischlik, Fiorella and Majek, Peter and Parapatics, Katja and Schmidl, Christian and Schuster, Michael and Penz, Thomas and Buckley, Dennis L. and Hudecz, Otto and Imre, Richard and Wang, Shuang-Yan and Maric, Hans Michael and Kralovics, Robert and Bennett, Keiryn L. and Mueller, Andre C. and Mechtler, Karl and Menche, Joerg and Bradner, James E. and Winter, Georg E. and Klavins, Kristaps and Casanova, Emilio and Bock, Christoph and Zuber, Johannes and Kubicek, Stefan (2019) MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation. NATURE GENETICS, 51 (6). 990-+. ISSN 1061-4036, 1546-1718
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NOVO THYMIDYLATE BIOSYNTHESIS; BET BROMODOMAIN PROTEINS; SELECTIVE-INHIBITION; HUMAN-CELLS; RESISTANCE; CHROMATIN; DISRUPTION; TARGET; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Apr 2020 08:47 |
| Last Modified: | 14 Apr 2020 08:47 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26929 |
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