UV-Protection Timer Controls Linkage between Stress and Pigmentation Skin Protection Systems

Hagar Malcov-Brog, Ayelet Alpert, Tamar Golan, Shivang Parikh, Alice Nordlinger, Francesca Netti, Danna Sheinboim, Iris Dror, Laetitia Thomas, Camille Cosson, Pinchas Gonen, Yury Stanevsky, Ronen Brenner, Tomer Perluk, Jacob Frand, Sharona Elgavish, Yuval Nevo, Dolev Rahat, Yuval Tabach, Mehdi Khaled*Shai S. Shen-Orr, Carmit Levy

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Skin sun exposure induces two protection programs: stress responses and pigmentation, the former within minutes and the latter only hours afterward. Although serving the same physiological purpose, it is not known whether and how these programs are coordinated. Here, we report that UVB exposure every other day induces significantly more skin pigmentation than the higher frequency of daily exposure, without an associated increase in stress responses. Using mathematical modeling and empirical studies, we show that the melanocyte master regulator, MITF, serves to synchronize stress responses and pigmentation and, furthermore, functions as a UV-protection timer via damped oscillatory dynamics, thereby conferring a trade-off between the two programs. MITF oscillations are controlled by multiple negative regulatory loops, one at the transcriptional level involving HIF1α and another post-transcriptional loop involving microRNA-148a. These findings support trait linkage between the two skin protection programs, which, we speculate, arose during furless skin evolution to minimize skin damage. Malcov-Brog et al. report that UVB exposure every other day induces more skin pigmentation than daily exposure. This reveals a trade-off between the two skin protection programs, pigmentation and stress response. MITF synchronizes skin protection programs and functions as a UV-protection timer via damped oscillatory dynamics, controlled by multiple negative regulatory loops.

Original languageAmerican English
Pages (from-to)444-456.e7
JournalMolecular Cell
Volume72
Issue number3
DOIs
StatePublished - 1 Nov 2018

Bibliographical note

Funding Information:
The authors gratefully thank Drs. Meenhard Herlyn and Levi Garraway for supplying melanoma cultures. C.L. gratefully thanks Dr. Ana Moshkovsky and Prof. Noga Kronfeld-Schor for useful discussions and Yuval and Omer Levy for exponential joy. C.L. acknowledges grant support from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 726225 ); the I-CORE Gene Regulation in Complex Human Disease Center no. 41/11 ; Israel Science Foundation (ISF) grant 129/13 ; Fritz Thyssen Stiftung ; the Israel Cancer Research Fund (ICRF) grant 2011-706-RCDA ; the Salomea (Mika) and Herman Berger Z”L Foundation ; and the United States-Israel Binational Science Foundation (BSF) grant 2011172 . H.M.-B. gratefully acknowledges the Shtacher Family award; The Naomi Foundation , through the Tel Aviv University GRTF Program; Dr. Eli Fisher for his generous scholarship; and Yoav Brog for the joint journey. Research by S.S.S-O. and A.A. was supported by Israel Science Foundation (ISF) grant 1365/12 . C.L. and S.S.S.-O. thank the Kavli Frontiers of Science Program for providing the opportunity for this collaboration. Research by M.K. and A.N. was supported by the Gustave Roussy foundation and Natixis. A.N. was supported by a fellowship from the French ministry of higher education and research.

Funding Information:
The authors gratefully thank Drs. Meenhard Herlyn and Levi Garraway for supplying melanoma cultures. C.L. gratefully thanks Dr. Ana Moshkovsky and Prof. Noga Kronfeld-Schor for useful discussions and Yuval and Omer Levy for exponential joy. C.L. acknowledges grant support from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 726225); the I-CORE Gene Regulation in Complex Human Disease Center no. 41/11; Israel Science Foundation (ISF) grant 129/13; Fritz Thyssen Stiftung; the Israel Cancer Research Fund (ICRF) grant 2011-706-RCDA; the Salomea (Mika) and Herman Berger Z”L Foundation; and the United States-Israel Binational Science Foundation (BSF) grant 2011172. H.M.-B. gratefully acknowledges the Shtacher Family award; The Naomi Foundation, through the Tel Aviv University GRTF Program; Dr. Eli Fisher for his generous scholarship; and Yoav Brog for the joint journey. Research by S.S.S-O. and A.A. was supported by Israel Science Foundation (ISF) grant 1365/12. C.L. and S.S.S.-O. thank the Kavli Frontiers of Science Program for providing the opportunity for this collaboration. Research by M.K. and A.N. was supported by the Gustave Roussy foundation and Natixis. A.N. was supported by a fellowship from the French ministry of higher education and research.

Publisher Copyright:
© 2018 The Authors

Keywords

  • MITF dynamics
  • UVB radiation
  • skin pigmentation
  • skin proliferation
  • trait linkage

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