HDAC3 ensures stepwise epidermal stratification via NCoR/SMRT-reliant mechanisms independent of its histone deacetylase activity
- Katherine M. Szigety1,2,
- Fang Liu2,
- Chase Y. Yuan2,
- Deborah J. Moran2,
- Jeremy Horrell2,
- Heather R. Gochnauer2,
- Ronald N. Cohen3,
- Jonathan P. Katz4,
- Klaus H. Kaestner5,
- John T. Seykora2,
- John W. Tobias6,
- Mitchell A. Lazar7,
- Mingang Xu8,9 and
- Sarah E. Millar2,8,9,10
- 1Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 2Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 3Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Illinois 60637, USA;
- 4Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 5Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 6Penn Genomic Analysis Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 7Institute for Diabetes, Obesity, and Metabolism, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 8Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 9Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 10Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Corresponding authors: sarah.millar{at}mssm.edu; mingang.xu{at}mssm.edu
Abstract
Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. The class I HDAC, HDAC3, is of particular interest because it plays divergent roles in different tissues by partnering with tissue-specific transcription factors. We found that HDAC3 is expressed broadly in embryonic epidermis and is required for its orderly stepwise stratification. HDAC3 protein stability in vivo relies on NCoR and SMRT, which function redundantly in epidermal development. However, point mutations in the NCoR and SMRT deacetylase-activating domains, which are required for HDAC3's enzymatic function, permit normal stratification, indicating that HDAC3's roles in this context are largely independent of its histone deacetylase activity. HDAC3-bound sites are significantly enriched for predicted binding motifs for critical epidermal transcription factors including AP1, GRHL, and KLF family members. Our results suggest that among these, HDAC3 operates in conjunction with KLF4 to repress inappropriate expression of Tgm1, Krt16, and Aqp3. In parallel, HDAC3 suppresses expression of inflammatory cytokines through a Rela-dependent mechanism. These data identify HDAC3 as a hub coordinating multiple aspects of epidermal barrier acquisition.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.333674.119.
- Received October 8, 2019.
- Accepted April 23, 2020.
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