title: A meeting of two chronobiological systems: circadian proteins Period1 and BMAL1 modulate the human hair cycle clock.
abstract: The hair follicle (HF) is a continuously remodeled mini organ that cycles between growth (anagen), regression (catagen), and relative quiescence (telogen). As the anagen-to-catagen transformation of microdissected human scalp HFs can be observed in organ culture, it permits the study of the unknown controls of autonomous, rhythmic tissue remodeling of the HF, which intersects developmental, chronobiological, and growth-regulatory mechanisms. The hypothesis that the peripheral clock system is involved in hair cycle control, i.e., the anagen-to-catagen transformation, was tested. Here we show that in the absence of central clock influences, isolated, organ-cultured human HFs show circadian changes in the gene and protein expression of core clock genes (CLOCK, BMAL1, and Period1) and clock-controlled genes (c-Myc, NR1D1, and CDKN1A), with Period1 expression being hair cycle dependent. Knockdown of either BMAL1 or Period1 in human anagen HFs significantly prolonged anagen. This provides evidence that peripheral core clock genes modulate human HF cycling and are an integral component of the human hair cycle clock. Specifically, our study identifies BMAL1 and Period1 as potential therapeutic targets for modulating human hair growth.
authors.affiliation: The Dermatology Centre, Salford Royal NHS Foundation Trust and the Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: Yusur
authors.initials: Y
authors.lastname: Al-Nuaimi
authors.affiliation: The Dermatology Centre, Salford Royal NHS Foundation Trust and the Institute of Inflammation and Repair, Manchester Academic Health Science Centre, 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: DE-MTA ''Lendulet'' Cell Physiology Group, Department of Physiology, University of Debrecen, Debrecen, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Bíró
authors.affiliation: The Dermatology Centre, Salford Royal NHS Foundation Trust and the Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: Iain S
authors.initials: IS
authors.lastname: Haslam
authors.affiliation: Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Philpott
authors.affiliation: DE-MTA ''Lendulet'' Cell Physiology Group, Department of Physiology, University of Debrecen, Debrecen, Hungary.
authors.forename: Balázs I
authors.initials: BI
authors.lastname: Tóth
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: Faculty of Life Sciences, Division of Biosciences, Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: Gerold
authors.initials: G
authors.lastname: Baier
authors.affiliation: The Dermatology Centre, Salford Royal NHS Foundation Trust and the Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: Rachel E B
authors.initials: REB
authors.lastname: Watson
authors.affiliation: Italian Institute of Technology, Genova, Italy.
authors.forename: Benedetto
authors.initials: B
authors.lastname: Grimaldi
authors.affiliation: Department of Dermatology, University of Luebeck, Luebeck, Germany.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Kloepper
authors.affiliation: The Dermatology Centre, Salford Royal NHS Foundation Trust and the Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; Department of Dermatology, University of Luebeck, Luebeck, Germany. Electronic address: ralf.paus@uksh.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Paus
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D020868:Gene Silencing; D018859:Hair Follicle / Q000166:cytology / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D056950:Period Circadian Proteins / Q000235:genetics* / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism; D012535:Scalp / Q000166:cytology / Q000254:growth & development / Q000502:physiology*
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C064353:NR1D1 protein, human; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; C539022:PER1 protein, human; D056950:Period Circadian Proteins; D020598:Proto-Oncogene Proteins c-myb; D056926:CLOCK Proteins; C538943:CLOCK protein, human