The Peripheral Clock Regulates Human Pigmentation

Jonathan A. Hardman, Desmond J. Tobin, Iain S. Haslam, Nilofer Farjo, Bessam Farjo, Yusur Al-Nuaimi, Benedetto Grimaldi, Ralf Paus

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Although the regulation of pigmentation is well characterized, it remains unclear whether cell-autonomous controls regulate the cyclic on-off switching of pigmentation in the hair follicle (HF). As human HFs and epidermal melanocytes express clock genes and proteins, and given that core clock genes (PER1, BMAL1) modulate human HF cycling, we investigated whether peripheral clock activity influences human HF pigmentation. We found that silencing BMAL1 or PER1 in human HFs increased HF melanin content. Furthermore, tyrosinase expression and activity, as well as TYRP1 and TYRP2 mRNA levels, gp100 protein expression, melanocyte dendricity, and the number gp100+ HF melanocytes, were all significantly increased in BMAL1 and/or PER1-silenced HFs. BMAL1 or PER1 silencing also increased epidermal melanin content, gp100 protein expression, and tyrosinase activity in human skin. These effects reflect direct modulation of melanocytes, as BMAL1 and/or PER1 silencing in isolated melanocytes increased tyrosinase activity and TYRP1/2 expression. Mechanistically, BMAL1 knockdown reduces PER1 transcription, and PER1 silencing induces phosphorylation of the master regulator of melanogenesis, microphthalmia-associated transcription factor, thus stimulating human melanogenesis and melanocyte activity in situ and in vitro. Therefore, the molecular clock operates as a cell-autonomous modulator of human pigmentation and may be targeted for future therapeutic strategies.

LanguageEnglish
Pages1053-1064
Number of pages12
JournalJournal of Investigative Dermatology
Volume135
Issue number4
DOIs
Publication statusPublished - Apr 2015
Externally publishedYes

Fingerprint

Melanocytes
Pigmentation
Hair Follicle
Monophenol Monooxygenase
Clocks
Melanins
Microphthalmia-Associated Transcription Factor
Human Activities
Phosphorylation
Proteins
Transcription
Modulators
Skin
Genes
Modulation
Messenger RNA

Cite this

Hardman, J. A., Tobin, D. J., Haslam, I. S., Farjo, N., Farjo, B., Al-Nuaimi, Y., ... Paus, R. (2015). The Peripheral Clock Regulates Human Pigmentation. Journal of Investigative Dermatology, 135(4), 1053-1064. https://doi.org/10.1038/jid.2014.442
Hardman, Jonathan A. ; Tobin, Desmond J. ; Haslam, Iain S. ; Farjo, Nilofer ; Farjo, Bessam ; Al-Nuaimi, Yusur ; Grimaldi, Benedetto ; Paus, Ralf. / The Peripheral Clock Regulates Human Pigmentation. In: Journal of Investigative Dermatology. 2015 ; Vol. 135, No. 4. pp. 1053-1064.
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Hardman, JA, Tobin, DJ, Haslam, IS, Farjo, N, Farjo, B, Al-Nuaimi, Y, Grimaldi, B & Paus, R 2015, 'The Peripheral Clock Regulates Human Pigmentation', Journal of Investigative Dermatology, vol. 135, no. 4, pp. 1053-1064. https://doi.org/10.1038/jid.2014.442

The Peripheral Clock Regulates Human Pigmentation. / Hardman, Jonathan A.; Tobin, Desmond J.; Haslam, Iain S.; Farjo, Nilofer; Farjo, Bessam; Al-Nuaimi, Yusur; Grimaldi, Benedetto; Paus, Ralf.

In: Journal of Investigative Dermatology, Vol. 135, No. 4, 04.2015, p. 1053-1064.

Research output: Contribution to journalArticle

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AU - Tobin, Desmond J.

AU - Haslam, Iain S.

AU - Farjo, Nilofer

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AU - Grimaldi, Benedetto

AU - Paus, Ralf

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Hardman JA, Tobin DJ, Haslam IS, Farjo N, Farjo B, Al-Nuaimi Y et al. The Peripheral Clock Regulates Human Pigmentation. Journal of Investigative Dermatology. 2015 Apr;135(4):1053-1064. https://doi.org/10.1038/jid.2014.442