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, Mitchell A. Lazar

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Article number54
JournalNature communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

Fingerprint

Hepatocyte Nuclear Factor 4
Co-Repressor Proteins
liver
Liver
Triglycerides
modules
proteins
lipid metabolism
Genes
homeostasis
deletion
Histone Deacetylases
genome
metabolism
Ablation
Metabolism
genes
ablation
Mass spectrometry
mice

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides. / Armour, Sean M.; Remsberg, Jarrett R.; Damle, Manashree; Sidoli, Simone; Ho, Wesley Y.; Li, Zhenghui; Garcia, Benjamin A.; Lazar, Mitchell A.

In: Nature communications, Vol. 8, No. 1, 54, 01.12.2017.

Research output: Contribution to journalArticle

Armour, SM, Remsberg, JR, Damle, M, Sidoli, S, Ho, WY, Li, Z, Garcia, BA & Lazar, MA 2017, 'An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides', Nature communications, vol. 8, no. 1, 54. https://doi.org/10.1038/s41467-017-00772-5
Armour, Sean M. ; Remsberg, Jarrett R. ; Damle, Manashree ; Sidoli, Simone ; Ho, Wesley Y. ; Li, Zhenghui ; Garcia, Benjamin A. ; Lazar, Mitchell A. / An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides. In: Nature communications. 2017 ; Vol. 8, No. 1.
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