A Mount Sinai research team, led by Sarah E. Millar, PhD, director of the Black Family Stem Cell Institute at Icahn School of Medicine, found one of the mechanisms that establish the skin as a protective barrier. This knowledge can be used in both understanding and treating skin conditions like eczema and psoriasis. The findings for this study were published in the journal Genes & Development.
The research team discovered the scaffolding protein histone deacetylase 3 (HDAC3) is needed for proper skin development and barrier formation. In the study, conducted on mice, researchers discovered that the mice lacking HDAC3 specifically in the epidermis failed to develop a functional skin barrier. These mice also died shortly after birth, and this was caused by dehydration.
"HDAC3 is particularly interesting to us, as it associates with different proteins in different tissue types to regulate its target genes," says Katherine Szigety, M.D., PhD, student in the Millar Lab and first author of the study. "While HDAC3 has been studied in diverse contexts, its role and transcriptional partners in the developing epidermis had not been identified until now."
The extensive research performed on HDAC3 not only builds on previous studies on related proteins, but it also shows how HDAC3 regulates expression of its target genes in the epidermis by interacting with multiple DNA-binding proteins. The team discovered that the mechanisms in the gene regulation are distinctly different from those involving HDAC1 and HDAC2.
"Unlike HDAC1 and HDAC2, HDAC3's functions in regulating epidermal development appear to be independent of its enzyme activity. Because clinically available HDAC inhibitors specifically block enzyme function, our findings suggest that the effects of treatment with an HDAC inhibitor might resemble loss of HDACs 1 and 2 in the skin, but perhaps not HDAC3," said Millar. "This may have important implications for the use of HDAC inhibitors in managing CTCL and other skin conditions. An exciting next step for our group will be to characterize the role of HDAC3 in skin disease."