An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides

Sean M. Armour, Jarrett R. Remsberg, Manashree Damle, Simone Sidoli, Wesley Y. Ho, Zhenghui Li, Benjamin A. Garcia and Mitchell A. Lazar ()
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Sean M. Armour: Perelman School of Medicine at the University of Pennsylvania
Jarrett R. Remsberg: Perelman School of Medicine at the University of Pennsylvania
Manashree Damle: Perelman School of Medicine at the University of Pennsylvania
Simone Sidoli: Perelman School of Medicine at the University of Pennsylvania
Wesley Y. Ho: Perelman School of Medicine at the University of Pennsylvania
Zhenghui Li: Perelman School of Medicine at the University of Pennsylvania
Benjamin A. Garcia: Perelman School of Medicine at the University of Pennsylvania
Mitchell A. Lazar: Perelman School of Medicine at the University of Pennsylvania

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract The histone deacetylase HDAC3 is a critical mediator of hepatic lipid metabolism, and liver-specific deletion of HDAC3 leads to fatty liver. To elucidate the underlying mechanism, here we report a method of cross-linking followed by mass spectrometry to define a high-confidence HDAC3 interactome in vivo that includes the canonical NCoR–HDAC3 complex as well as Prospero-related homeobox 1 protein (PROX1). HDAC3 and PROX1 co-localize extensively on the mouse liver genome, and are co-recruited by hepatocyte nuclear factor 4α (HNF4α). The HDAC3–PROX1 module controls the expression of a gene program regulating lipid homeostasis, and hepatic-specific ablation of either component increases triglyceride content in liver. These findings underscore the importance of specific combinations of transcription factors and coregulators in the fine tuning of organismal metabolism.

Date: 2017
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DOI: 10.1038/s41467-017-00772-5

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