A research team at Mount Sinai Hospital in New York City has identified one of the mechanisms that establish the skin as a protective barrier. In a study published online ahead of print in the journal Genes & Development (May 28, 2020), the authors suggest the breakthrough could be critical to understanding and treating skin conditions such as eczema and psoriasis.
Led by Dr. Sarah E. Millar, the director of the Black Family Stem Cell Institute at the Icahn School of Medicine at Mount Sinai, investigators found that the scaffolding protein, histone deacetylase 3 (HDAC3), is essential for skin development and barrier formation.
Using a mouse model, researchers discovered that mice lacking HDAC3, specifically in the epidermis, fail to develop functional skin barrier and die shortly after birth due to dehydration.
Research conducted by the study’s authors describes a complex process where the HDAC regulates expression of its target genes in the epidermis by interacting with multiple DNA-binding proteins.
“HDAC3 is particularly interesting to us, as it associates with different proteins in different tissue types to regulate its target genes,” said Katherine Szigety, a PhD student in the Millar Lab, in a press release. Szigety is the first author on 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.”
HDAC3 is part of a family of epigenetic regulators known as histone deacetylases (HDACs) which control gene expression by changing the structure of genetic material.
Dr. Millar’s lab is studying HDACs because a group of drugs called HDAC inhibitors are used to treat cutaneous T-cell lymphoma (CTCL). The lab’s research on HDAC3 builds on their previous studies of the related proteins HDAC1 and HDAC2 in skin development.
The investigators found that the mechanisms by which HDAC3 regulates target gene expression are distinctly different from those involving HDAC1 and HDAC2.
“Unlike HDACs 1 and 2, 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 Dr. 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.”