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Building links between chromatin and metabolism

MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation

This artistic rendering depicts a role for folate metabolism in BRD4-mediated transcription. The folate metabolic enzyme MTHFD1 is recruited to chromatin through physical interaction with BRD4. Through its enzymatic activity, MTHFD1 provides one-carbon intermediates, which form the building blocks for several important metabolite classes in the nucleus, including purines, which are incorporated into RNA during transcription.

See Sdelci et al.

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.

Nature Genetics volume 51, pages990–998 (2019)

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