title: The peripheral clock regulates human pigmentation.
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.
authors.affiliation: The Centre for Dermatology Research, Institute of Inflammation and Repair, University of Manchester, Manchester, UK; Doctoral Training Centre in Integrative Systems Biology, Manchester Institute of Biotechnology, University of Manchester, Manchester, UK.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Hardman
authors.affiliation: Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, UK.
authors.forename: Desmond J
authors.initials: DJ
authors.lastname: Tobin
authors.affiliation: The Centre for Dermatology Research, Institute of Inflammation and Repair, University of Manchester, Manchester, UK.
authors.forename: Iain S
authors.initials: IS
authors.lastname: Haslam
authors.affiliation: Farjo Medical Centre, Manchester, UK.
authors.forename: Nilofer
authors.initials: N
authors.lastname: Farjo
authors.affiliation: Farjo Medical Centre, Manchester, UK.
authors.forename: Bessam
authors.initials: B
authors.lastname: Farjo
authors.affiliation: The Centre for Dermatology Research, Institute of Inflammation and Repair, University of Manchester, Manchester, UK.
authors.forename: Yusur
authors.initials: Y
authors.lastname: Al-Nuaimi
authors.affiliation: Department of Drug Discovery and Development, Instituto Italiano di Tecnologia (IIT), Genoa, Italy.
authors.forename: Benedetto
authors.initials: B
authors.lastname: Grimaldi
authors.affiliation: The Centre for Dermatology Research, Institute of Inflammation and Repair, University of Manchester, Manchester, UK; Department of Dermatology, University of Muenster, Muenster, Germany. Electronic address: ralf.paus@manchester.ac.uk.
authors.forename: Ralf
authors.initials: R
authors.lastname: Paus
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism*; D001683:Biological Clocks; D004817:Epidermis / Q000378:metabolism; D020868:Gene Silencing; D018859:Hair Follicle / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D008543:Melanins / Q000737:chemistry / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000378:metabolism; D056950:Period Circadian Proteins / Q000378:metabolism*; D010858:Pigmentation; D012867:Skin / Q000378:metabolism; D058951:gp100 Melanoma Antigen / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; C539022:PER1 protein, human; D056950:Period Circadian Proteins; D058951:gp100 Melanoma Antigen; D014442:Monophenol Monooxygenase