TY - JOUR
T1 - An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides
AU - Armour, Sean M.
AU - Remsberg, Jarrett R.
AU - Damle, Manashree
AU - Sidoli, Simone
AU - Ho, Wesley Y.
AU - Li, Zhenghui
AU - Garcia, Benjamin A.
AU - Lazar, Mitchell A.
N1 - Funding Information:
We thank K. Kaestner (University of Pennsylvania) for providing the Hnf4αfl/fl mice. We acknowledge the Functional Genomics Core and the Viral Vector Core of the Penn Diabetes Research Center (P30DK19525) for next-generation sequencing and virus production. We thank the Molecular Pathology and Imaging Core of the University of Pennsylvania (P30DK050306) for histology. We thank C.L. Lanzillotta, X.J. Cao, Z. Sun, M. Emmett, K. Kulej, P.M. Titchenell, D. Steger, and D. Cohen for technical support and insightful discussions on the project. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants F32DK102284 (to S.M.A.) and R37DK43806 (to M.A.L.), and National Institute of General Medical Sciences Grants T32GM008275 (to J.R.R.) and R01GM110174 (to B.A.G.).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85029475426&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-00772-5
DO - 10.1038/s41467-017-00772-5
M3 - Article
C2 - 28916805
AN - SCOPUS:85029475426
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 549
ER -