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

Balmer, Pierre; Hariton, William V. J.; Sayar, Beyza; Jagannathan, Vidhya; Galichet, Arnaud; Leeb, Tosso; Roosje, Petra; Müller, Eliane Jasmine (2021). SUV39H2 epigenetic silencing controls fate conversion of epidermal stem and progenitor cells. Journal of cell biology, 220(4) Rockefeller Institute Press 10.1083/jcb.201908178

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Epigenetic histone trimethylation on lysine 9 (H3K9me3) represents a major molecular signal for genome stability and gene silencing conserved from worms to man. However, the functional role of the H3K9 trimethylases SUV39H1/2 in mammalian tissue homeostasis remains largely unknown. Here, we use a spontaneous dog model with monogenic inheritance of a recessive SUV39H2 loss-of-function variant and impaired differentiation in the epidermis, a self-renewing tissue fueled by stem and progenitor cell proliferation and differentiation. Our results demonstrate that SUV39H2 maintains the stem and progenitor cell pool by restricting fate conversion through H3K9me3 repressive marks on gene promoters encoding components of the Wnt/p63/adhesion axis. When SUV39H2 function is lost, repression is relieved, and enhanced Wnt activity causes progenitor cells to prematurely exit the cell cycle, a process mimicked by pharmacological Wnt activation in primary canine, human, and mouse keratinocytes. As a consequence, the stem cell growth potential of cultured SUV39H2-deficient canine keratinocytes is exhausted while epidermal differentiation and genome stability are compromised. Collectively, our data identify SUV39H2 and potentially also SUV39H1 as major gatekeepers in the delicate balance of progenitor fate conversion through H3K9me3 rate-limiting road blocks in basal layer keratinocytes.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Pathologie > Forschungsgruppe Dermatologie
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV) > DKV - Dermatology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Dermatology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Research Foci > DermFocus
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV)
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Balmer, Pierre; Hariton, William Vincent; Sayar, Beyza; Jagannathan, Vidya; Galichet, Arnaud; Leeb, Tosso; Roosje, Petra and Müller, Eliane Jasmine

Subjects:

600 Technology > 610 Medicine & health
600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
500 Science > 590 Animals (Zoology)

ISSN:

0021-9525

Publisher:

Rockefeller Institute Press

Language:

English

Submitter:

Tosso Leeb

Date Deposited:

23 Feb 2021 11:49

Last Modified:

25 Feb 2021 13:41

Publisher DOI:

10.1083/jcb.201908178

PubMed ID:

33604655

BORIS DOI:

10.48350/152613

URI:

https://boris.unibe.ch/id/eprint/152613

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