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

Nature Structural & Molecular Biology volume 20, pages 182–187 (2013)Cite this article

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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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Figure 1: NS-DADm mice expressed normal levels of HDAC3.
Figure 2: HDAC3 was enzymatically inactive in various tissues of NS-DADm mice.
Figure 3: Genomic localization of HDAC3 was significantly reduced in NS-DADm mice.
Figure 4: Local histone acetylation was increased in NS-DADm mice.
Figure 5: The liver phenotype of NS-DADm mice was more modest than that for mice lacking hepatic HDAC3.
Figure 6: Gene expression changes in NS-DADm livers were mild compared to those in HDAC3 protein depletion.

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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.

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Authors and 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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  1. Seo-Hee You
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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.

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Correspondence to Mitchell A Lazar.

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You, SH., Lim, HW., Sun, Z. et al. Nuclear receptor co-repressors are required for the histone-deacetylase activity of HDAC3 in vivo. Nat Struct Mol Biol 20, 182–187 (2013). https://doi.org/10.1038/nsmb.2476

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