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BRD4 is necessary for epidermal differentiation

ABSTRACT: BRD4 is an epigenetic reader known to bind to acetylated lysines on histones and transcription factors, and it has been implicated in recruiting transcriptional machinery to promote differentiation gene expression in multiple cellular contexts. This activity is dependant on proper BRD4 localization to active promoters and enhancers, which is dependant on a variety of factors including lineage determining transcription factors (LDTFs). We found BRD4 to be necessary for epidermal differentiation, during which it shares many chromatin binding sites with a variety of epidermal lineage-determining transcription factors (LDTF's). BRD4 also regulates a similar differentiation related transcriptional program with the epidermal LDTF KLF4.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140992 | GEO | 2020/04/03

REPOSITORIES: GEO

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Project 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.

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BRD4 is necessary for epidermal differentiation

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