Article | Published:

Nuclear receptor co-repressors are required for the histone-deacetylase activity of HDAC3 in vivo

Nature Structural & Molecular Biology volume 20, pages 182187 (2013) | Download Citation

Abstract

Histone deacetylase 3 (HDAC3) is an epigenome-modifying enzyme that is required for normal mouse development and tissue-specific functions. In vitro, HDAC3 protein itself has minimal enzyme activity but gains its histone-deacetylation function from stable association with the conserved deacetylase-activating domain (DAD) contained in nuclear receptor co-repressors NCOR1 and SMRT. Here we show that HDAC3 enzyme activity is undetectable in mice bearing point mutations in the DAD of both NCOR1 and SMRT (NS-DADm), despite having normal levels of HDAC3 protein. Local histone acetylation is increased, and genomic HDAC3 recruitment is reduced though not abrogated. Notably, NS-DADm mice are born and live to adulthood, whereas genetic deletion of HDAC3 is embryonic lethal. These findings demonstrate that nuclear receptor co-repressors are required for HDAC3 enzyme activity in vivo and suggest that a deacetylase-independent function of HDAC3 may be required for life.

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Acknowledgements

This work was supported by R37DK43806 (M.A.L.) and RC1DK86239 (M.A.L.) from the US National Institute of Diabetes, and Digestive and Kidney Diseases, and by a Mentor Based Fellowship from the American Diabetes Association (M.A.L. and S.-H.Y.). We thank T. Alenghat (Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA) for early versions of the SMRT DAD targeting construct and K. Kaestner for help with gene targeting in C57BL/6 embryonic stem cells. We also acknowledge the Functional Genomics Core of the Penn Diabetes Research Center (DK19525), directed by K. Kaestner and J. Schug, for next generation sequencing.

Author information

Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Seo-Hee You
    • , Zheng Sun
    • , Molly Broache
    •  & Mitchell A Lazar
  2. The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Seo-Hee You
    • , Hee-Woong Lim
    • , Zheng Sun
    • , Molly Broache
    • , Kyoung-Jae Won
    •  & Mitchell A Lazar
  3. Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Hee-Woong Lim
    • , Kyoung-Jae Won
    •  & Mitchell A Lazar

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Contributions

S.-H.Y. and M.A.L. conceived of the hypothesis and designed the experiments. S.-H.Y., Z.S. and M.B. performed the experiments. H.-W.L. and K.-J.W. analyzed bioinformatics data. S.-H.Y., Z.S. and M.A.L. analyzed and interpreted the data. S.-H.Y. and M.A.L. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mitchell A Lazar.

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https://doi.org/10.1038/nsmb.2476

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