Abstract
Ultraviolet (UV) radiation is a prime environmental stressor that our epidermis is exposed to on a daily basis. To avert UV-induced damage, epidermal stem cells (EpSCs) become pigmented via a process of heterotypic interaction between melanocytes and EpSCs; however, the molecular mechanisms of this interaction are not well understood. In this study, we show that the function of a key chromatin regulator, the Polycomb complex, was reduced upon UV exposure in human and mouse epidermis. Genetic ablation of key Polycomb subunits in murine EpSCs, mimicking depletion upon UV exposure, results in an increased number of epidermal melanocytes and subsequent epidermal pigmentation. Genome-wide transcriptional and chromatin studies show that Polycomb regulates the expression of UV-responsive genes and identifies type II collagen (COL2A1) as a critical secreted regulator of melanogenesis and epidermal pigmentation. Together, our findings show how UV exposure induces Polycomb-mediated changes in EpSCs to affect melanocyte behavior and promote epidermal pigmentation.
| Original language | English |
|---|---|
| Pages (from-to) | 2547-2561.e8 |
| Journal | Developmental Cell |
| Volume | 56 |
| Issue number | 18 |
| DOIs | |
| State | Published - Sep 27 2021 |
Bibliographical note
Publisher Copyright:© 2021 Elsevier Inc.
Funding
We thank Sergei Ezhkov and all Ezhkova lab members for their help and critical suggestions. We thank Dr. Miguel Vidal for the Ring1a-null and Ring1b-floxed mice, Drs. Weipeng Mu and Terry Magnuson for the Eed-floxed mice, and Dr. Tudorita Tumbar for the K14-CreERT2 mice. We thank Dr. Emily Bernstein for B16F0 cells and Penn SBDRC for human skin samples. We also thank the Flow Cytometry Core, the Electron Microscopy Facility, and the Tisch Cancer Center sequencing facility at the ISMMS. The research reported here was supported by the National Institutes of Health under award numbers R01AR069078 (to E.E.), R01HL148128 and R01HL153920 (to D. Zheng), R01GM122749 and P30CA196521 (to J.J.), an endowed professorship from the ISMMS (to J.J.), the Tisch Cancer Institute P30 Cancer Support Grant (to E.E.), and the NYSTEM Institutional Training program C32561GG (to P.F.). M.-Y.L. and E.E. conceived and designed the experiments. M.-Y.L. P.F. and I.C. performed the experiments. M.-Y.L. E.E. H.L. P.M.G.Jr. and D.Z. performed the bioinformatic analyses. H.K. provided the Ring1a-null and Ring1b-floxed mice. J.S. provided the lentiviral overexpression constructs. W.A.B. provided the Ring1b I53A mice. M.-Y.L. P.M.G.Jr. C.B. I.C. J.S. D.Z. and E.E. analyzed the data. H.P. and J.A.D. performed UVB irradiation experiments on mice and provided skins. M.-Y.L. P.F. and E.E. wrote the manuscript with input from all other authors. The Jin laboratory received research funds from Celgene Corporation, Levo Therapeutics, and Cullgen. J.J. is a cofounder, equity shareholder, and consultant of Cullgen. We thank Sergei Ezhkov and all Ezhkova lab members for their help and critical suggestions. We thank Dr. Miguel Vidal for the Ring1a-null and Ring1b-floxed mice, Drs. Weipeng Mu and Terry Magnuson for the Eed-floxed mice, and Dr. Tudorita Tumbar for the K14-CreERT2 mice. We thank Dr. Emily Bernstein for B16F0 cells and Penn SBDRC for human skin samples. We also thank the Flow Cytometry Core, the Electron Microscopy Facility, and the Tisch Cancer Center sequencing facility at the ISMMS. The research reported here was supported by the National Institutes of Health under award numbers R01AR069078 (to E.E.), R01HL148128 and R01HL153920 (to D. Zheng), R01GM122749 and P30CA196521 (to J.J.), an endowed professorship from the ISMMS (to J.J.), the Tisch Cancer Institute P30 Cancer Support Grant (to E.E.), and the NYSTEM Institutional Training program C32561GG (to P.F.).
| Funders | Funder number |
|---|---|
| New York State Stem Cell Science | |
| Penn SBDRC | |
| Tisch Cancer Institute | |
| Celgene | |
| Levo Therapeutics | |
| National Institutes of Health (NIH) | R01HL153920, R01AR069078, R01HL148128, R01GM122749, P30CA196521 |
| Japan Society for the Promotion of Science | 19H05745 |
Keywords
- Polycomb
- UV
- epidermis
- melanocyte
- pigmentation
- stem cell
- type II collagen
ASJC Scopus subject areas
- Molecular Biology
- General Biochemistry, Genetics and Molecular Biology
- Developmental Biology
- Cell Biology