SUV39H2 epigenetic silencing controls fate conversion of epidermal stem and progenitor cells

Monogenetic disorders that occur spontaneously provide researchers the opportunity to backtrack clinical signs to default tissue homeostasis, associate them with a genetic variant and identify unknown underlying mechanisms. The outermost layer of the skin is the epidermis which is considered an interesting model for studying homeostatic processes, because it has the ability to self-renew in a short period of time. In addition, homeostatic processes in the epidermis can be modeled in cultured keratinocytes which essentially follow the predefined epidermal differentiation program. Epigenetic histone trimethylation on lysine 9 (H3K9me3) is an important molecular signal for genome stability and gene silencing conserved from worms to man. The SUV39H1 and SUV39H2 lysine methyltransferases are mammalian enzymes that catalyze the addition of H3K9me3 marks in euchromatin, pericentric heterochromatin, and at telomeres. Their function in regulating homeostatic processes, especially in the skin remains unclear and needs to be further elucidated.

In a new study, Swiss scientists from the University of Bern: Dr. Pierre Balmer, Dr. William Hariton, Dr .Beyza  Sayar, Dr. Arnaud Galichet, Professor Vidhya Jagannathan, Professor Tosso Leeb,  Professor Petra Roosje and Professor Eliane J. Müller explored the functional activity and significance of SUV39H2-mediated H3K9me3 repressive marks in epidermal homeostasis. Their results showed that SUV39H2 is involved in epidermal homeostasis through the maintenance of the stem and progenitor cell pool by restricting fate conversion via H3K9me3 repressive marks on gene promoters encoding components of the Wnt/p63/adhesion axis. The original research article is published in the Journal of Cell Biology.

The authors found a graded pattern of H3K9me3 marks, which were highest in the nuclei of basal epidermal keratinocytes upon the examination of biopsies from control Labrador retrievers. However, H3K9me3 marks were absent in the nasal planum epidermis of dogs with hereditary nasal parakeratosis. They found that the repression of H3K9me3 marks in the epidermis of the nasal planum was introduced majorly by the enzyme SUV39H2.

When the research team examined the RNA and protein expression profile in dogs with hereditary nasal parakeratosis, they showed premature cell cycle exit, deregulated p53, Wnt, and Notch signaling with impaired terminal differentiation. Moreover, premature progenitor fate conversion paired with a senescence-like state was exhibited by the nasal keratinocytes isolated from dogs with hereditary nasal parakeratosis.

The authors demonstrated that the hereditary nasal parakeratosis phenotype was caused by the functionally inactive SUV39H2 variant. This resulted in a failure to slow the fate conversion of progenitor cells and modulate the speed of cell cycle exit. While the Wnt/p63/adhesion signaling pathways were found to be epigenetically suppressed by SUV39H2 under control conditions, elevated Wnt signaling was identified as a major cause of hereditary nasal parakeratosis and a key mediator of cell fate conversion at cell cycle exit in epidermal keratinocytes. A lack of a hereditary nasal parakeratosis phenotype in the skin correlated with low SUV39H2 but conversely high SUV39H1 levels.  In the absence of significant SUV39H1 levels, loss of SUV39H2 function affected stem cell potential.

Through this landmark research, the authors emphasized the vital role SUV39H2 plays in modulating stem cell activation and progenitor fate conversion of epidermal keratinocytes. The mechanism is demonstrated to be through rate-limiting H3K9me3 roadblocks in epidermal progenitor cells resulting in the timely repression of major signaling pathways of the Wnt/p63/adhesion axis. As confirmed in this study, these signaling pathways also drive fate conversion of stem/progenitor cells of human keratinocytes and a role of SUV39H2 in this process is compatible with the overexpression of SUV39H2 in a variety of human cancer types. Hence, the findings from this study serve as a foundation to further the understanding of homeostasis in other tissues and offer new strategies for diagnosis and therapy of pathological conditions in animals and humans.