PXD013090

PXD013090 is an original dataset announced via ProteomeXchange.

Title	Chromatin isolation for mass spectrometry
Description	The histone acetyl-reader 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. 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, and pharmacologic 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. BRD4 is an important chromatin regulator with roles in gene regulation, DNA damage, cell proliferation and cancer progression1-4. The protein is recruited to distinct genomic loci by the interaction of its tandem bromodomains with acetylated lysines on histones and other nuclear proteins5. There, BRD4 acts as a transcriptional activator by P-TEFb-mediated stimulation of transcriptional elongation6. The activating function of BRD4 on key driver oncogenes like MYC have made this epigenetic enzyme an important therapeutic target in both BRD4 translocated and BRD4 wild-type cancers3,7-12, and at least seven bromodomain inhibitors have reached the clinical stage13. Genome-wide studies have identified the role of BRD4-induced epigenetic heterogeneity in cancer cell resistance14, and factors defining BRD4 inhibitor response15,16. However, despite its clinical importance and the broad role of BRD4 in chromatin organization, surprisingly little is known about factors that are directly required for BRD4 function. To systematically expand the list of known BRD4 interactors5 and to characterize proteins directly required for BRD4 function, we developed a strategy of two complementary screens for genetic and physical partners of BRD4. The two approaches converge on a single factor, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1). Our description of a transcriptional role for this C-1-tetrahydrofolate synthase highlights a direct connection between nuclear folate metabolism and cancer regulation.
HostingRepository	PRIDE
AnnounceDate	2019-12-13
AnnouncementXML	Submission_2019-12-13_04:00:04.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD013090
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Peter Májek
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex; Oxidation; Carbamidomethyl
Instrument	Orbitrap Fusion Lumos; LTQ Orbitrap Velos; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-03-14 00:31:09	ID requested
1	2019-04-04 05:46:54	announced
⏵ 2	2019-12-13 04:00:12	announced	2019-12-13: Updated publication reference for PubMed record(s): 31133746.

Sdelci S, Rendeiro AF, Rathert P, You W, Lin JG, Ringler A, Hofst, ä, tter G, Moll HP, G, ü, rtl B, Farlik M, Schick S, Klepsch F, Oldach M, Buphamalai P, Schischlik F, M, á, jek P, Parapatics K, Schmidl C, Schuster M, Penz T, Buckley DL, Hudecz O, Imre R, Wang SY, Maric HM, Kralovics R, Bennett KL, M, ü, ller AC, Mechtler K, Menche J, Bradner JE, Winter GE, Klavins K, Casanova E, Bock C, Zuber J, Kubicek S, MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation. Nat Genet, 51(6):990-998(2019) [pubmed]

curator keyword: Technical

submitter keyword: MTHFD1, transcription, folate metabolism, BRD4, gene regulation

Stefan Kubicek
contact affiliation	CeMM, Research Center for Molecular Medicine, Austrian Academy of Sciences, Austria
contact email	skubicek@cemm.at
lab head
Peter Májek
contact affiliation	CeMM, Reserach Center for Molecular Medicine
contact email	pmajek@cemm.at
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD013090
     1. Label: PRIDE project
     2. Name: Chromatin isolation for mass spectrometry