HDAC3 ensures stepwise epidermal stratification via NCoR/SMRT-reliant mechanisms independent of its histone deacetylase activity

Genes Dev. 2020 Jul 1;34(13-14):973-988. doi: 10.1101/gad.333674.119. Epub 2020 May 28.


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.

Keywords: HDAC3; KLF4; NCoR; SMRT; chromatin; epidermal barrier; epidermis; epigenetic; histone deacetylase; mouse.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Embryo, Mammalian
  • Epidermal Cells / cytology*
  • Epidermis / embryology*
  • Gene Deletion
  • Gene Expression Regulation, Developmental
  • Genes, Lethal / genetics
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism*
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Nuclear Receptor Co-Repressor 1 / genetics
  • Nuclear Receptor Co-Repressor 1 / metabolism
  • Nuclear Receptor Co-Repressor 2 / genetics
  • Nuclear Receptor Co-Repressor 2 / metabolism
  • Protein Interaction Domains and Motifs / genetics
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism


  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • Ncor1 protein, mouse
  • Ncor2 protein, mouse
  • Nuclear Receptor Co-Repressor 1
  • Nuclear Receptor Co-Repressor 2
  • Rela protein, mouse
  • Transcription Factor RelA
  • Histone Deacetylases
  • histone deacetylase 3