An HDAC3-PROX1 Corepressor Module Acts on HNF4α to Control Hepatic Triglycerides

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Sep 17

PMID 28916805

Citations 41

Authors

Sean M Armour

Jarrett R Remsberg

Manashree Damle

Simone Sidoli

Wesley Y Ho

Zhenghui Li

Benjamin A Garcia

Mitchell A Lazar

Affiliations

Soon will be listed here.

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.HDAC3 is a critical mediator of hepatic lipid metabolism and its loss leads to fatty liver. Here, the authors characterize the liver HDAC3 interactome in vivo, provide evidence that HDAC3 interacts with PROX1, and show that HDAC3 and PROX1 control expression of genes regulating lipid homeostasis.

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References

Sun Z, Miller R, Patel R, Chen J, Dhir R, Wang H . Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat Med. 2012; 18(6):934-42. PMC: 3411870. DOI: 10.1038/nm.2744. View

Lim H, Uhlenhaut N, Rauch A, Weiner J, Hubner S, Hubner N . Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo. Genome Res. 2015; 25(6):836-44. PMC: 4448680. DOI: 10.1101/gr.188581.114. View

Mo A, Mukamel E, Davis F, Luo C, Henry G, Picard S . Epigenomic Signatures of Neuronal Diversity in the Mammalian Brain. Neuron. 2015; 86(6):1369-84. PMC: 4499463. DOI: 10.1016/j.neuron.2015.05.018. View

Calkin A, Tontonoz P . Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol. 2012; 13(4):213-24. PMC: 3597092. DOI: 10.1038/nrm3312. View

Lecompte S, Pasquetti G, Hermant X, Grenier-Boley B, Gonzalez-Gross M, De Henauw S . Genetic and molecular insights into the role of PROX1 in glucose metabolism. Diabetes. 2013; 62(5):1738-45. PMC: 3636631. DOI: 10.2337/db12-0864. View

Shimizu H, Astapova I, Ye F, Bilban M, Cohen R, Hollenberg A . NCoR1 and SMRT play unique roles in thyroid hormone action in vivo. Mol Cell Biol. 2014; 35(3):555-65. PMC: 4285426. DOI: 10.1128/MCB.01208-14. View

Berger J, Charron M, Silver D . Major facilitator superfamily domain-containing protein 2a (MFSD2A) has roles in body growth, motor function, and lipid metabolism. PLoS One. 2012; 7(11):e50629. PMC: 3510178. DOI: 10.1371/journal.pone.0050629. View

Wang Y, Zhang Y, Qian H, Lu J, Zhang Z, Min X . The g0/g1 switch gene 2 is an important regulator of hepatic triglyceride metabolism. PLoS One. 2013; 8(8):e72315. PMC: 3741160. DOI: 10.1371/journal.pone.0072315. View

Bantscheff M, Hopf C, Savitski M, Dittmann A, Grandi P, Michon A . Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat Biotechnol. 2011; 29(3):255-65. DOI: 10.1038/nbt.1759. View

10.

Remsberg J, Ediger B, Ho W, Damle M, Li Z, Teng C . Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion. Mol Metab. 2017; 6(1):30-37. PMC: 5220396. DOI: 10.1016/j.molmet.2016.11.007. View

11.

Joshi P, Greco T, Guise A, Luo Y, Yu F, Nesvizhskii A . The functional interactome landscape of the human histone deacetylase family. Mol Syst Biol. 2013; 9:672. PMC: 3964310. DOI: 10.1038/msb.2013.26. View

12.

Steffensen K, Holter E, Bavner A, Nilsson M, Pelto-Huikko M, Tomarev S . Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ-F1 homologue. EMBO Rep. 2004; 5(6):613-9. PMC: 1299067. DOI: 10.1038/sj.embor.7400147. View

13.

Lai F, Gardini A, Zhang A, Shiekhattar R . Integrator mediates the biogenesis of enhancer RNAs. Nature. 2015; 525(7569):399-403. PMC: 4718573. DOI: 10.1038/nature14906. View

14.

Lengler J, Krausz E, Tomarev S, Prescott A, Quinlan R, Graw J . Antagonistic action of Six3 and Prox1 at the gamma-crystallin promoter. Nucleic Acids Res. 2001; 29(2):515-26. PMC: 29665. DOI: 10.1093/nar/29.2.515. View

15.

Bararia D, Kwok H, Welner R, Numata A, Sarosi M, Yang H . Acetylation of C/EBPα inhibits its granulopoietic function. Nat Commun. 2016; 7:10968. PMC: 4814574. DOI: 10.1038/ncomms10968. View

16.

Whyte W, Bilodeau S, Orlando D, Hoke H, Frampton G, Foster C . Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature. 2012; 482(7384):221-5. PMC: 4144424. DOI: 10.1038/nature10805. View

17.

Harvey N, Srinivasan R, Dillard M, Johnson N, Witte M, Boyd K . Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nat Genet. 2005; 37(10):1072-81. DOI: 10.1038/ng1642. View

18.

Knutson S, Chyla B, Amann J, Bhaskara S, Huppert S, Hiebert S . Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J. 2008; 27(7):1017-28. PMC: 2323257. DOI: 10.1038/emboj.2008.51. View

19.

Tilg H, Moschen A, Roden M . NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol. 2016; 14(1):32-42. DOI: 10.1038/nrgastro.2016.147. View

20.

Zhang J, Kalkum M, Chait B, Roeder R . The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Mol Cell. 2002; 9(3):611-23. DOI: 10.1016/s1097-2765(02)00468-9. View