title: Thyroxine differentially modulates the peripheral clock: lessons from the human hair follicle.
abstract: The human hair follicle (HF) exhibits peripheral clock activity, with knock-down of clock genes (BMAL1 and PER1) prolonging active hair growth (anagen) and increasing pigmentation. Similarly, thyroid hormones prolong anagen and stimulate pigmentation in cultured human HFs. In addition they are recognized as key regulators of the central clock that controls circadian rhythmicity. Therefore, we asked whether thyroxine (T4) also influences peripheral clock activity in the human HF. Over 24 hours we found a significant reduction in protein levels of BMAL1 and PER1, with their transcript levels also decreasing significantly. Furthermore, while all clock genes maintained their rhythmicity in both the control and T4 treated HFs, there was a significant reduction in the amplitude of BMAL1 and PER1 in T4 (100 nM) treated HFs. Accompanying this, cell-cycle progression marker Cyclin D1 was also assessed appearing to show an induced circadian rhythmicity by T4 however, this was not significant. Contrary to short term cultures, after 6 days, transcript and/or protein levels of all core clock genes (BMAL1, PER1, clock, CRY1, CRY2) were up-regulated in T4 treated HFs. BMAL1 and PER1 mRNA was also up-regulated in the HF bulge, the location of HF epithelial stem cells. Together this provides the first direct evidence that T4 modulates the expression of the peripheral molecular clock. Thus, patients with thyroid dysfunction may also show a disordered peripheral clock, which raises the possibility that short term, pulsatile treatment with T4 might permit one to modulate circadian activity in peripheral tissues as a target to treat clock-related disease.
authors.affiliation: The Dermatology Centre, Institute of Inflammation and Repair, University of Manchester, Manchester, United Kingdom; Doctoral Training Centre in Integrative Systems Biology, Manchester Interdisciplinary Bio centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Hardman
authors.affiliation: The Dermatology Centre, Institute of Inflammation and Repair, University of Manchester, Manchester, United Kingdom.
authors.forename: Iain S
authors.initials: IS
authors.lastname: Haslam
authors.affiliation: The Farjo Hair Institute, Manchester, United Kingdom.
authors.forename: Nilofer
authors.initials: N
authors.lastname: Farjo
authors.affiliation: The Farjo Hair Institute, Manchester, United Kingdom.
authors.forename: Bessam
authors.initials: B
authors.lastname: Farjo
authors.affiliation: The Dermatology Centre, Institute of Inflammation and Repair, University of Manchester, Manchester, United Kingdom; Department of Dermatology, University of Muenster, Muenster, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Paus
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D001683:Biological Clocks / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D018859:Hair Follicle / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D009924:Organ Culture Techniques; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013974:Thyroxine / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; C530104:CCND1 protein, human; C539022:PER1 protein, human; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D019938:Cyclin D1; D056926:CLOCK Proteins; C538943:CLOCK protein, human; D013974:Thyroxine
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