Chronobiology of the hair follicle:Dissecting the role of BMAL1 and PER1 in the control of human hair growth and pigmentation

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Abstract

The hair follicle (HF) is a human mini-organ that autonomously cycles between phases of growth (anagen), regression (catagen) and relative quiescence (telogen). Whilst many molecular controls are now appreciated to influence hair cycle, what ultimately choreographs the switch between each cycle stage is yet to be elucidated. With the increasing link between molecular clock activities in controlling local tissue physiology, we began by studying the hypothesis that the human HF has a functional molecular clock. Utilising human HF organ culture, qRT-PCR and immunofluorescence we found that the HF does indeed have oscillating clock gene expression over 24 and 48 hours in situ, separate from the suprachiasmatic-nucleus. Moreover, core clock proteins BMAL1 and PER1 are expressed in the human HF with PER1 increasing as HFs enter catagen. Next utilising siRNA mediated gene knock-down of either BMAL1 or PER1 in situ, we were able to show that silencing either clock gene leads to anagen prolongation in cultured HFs, demonstrating that the molecular clock modulates the human hair cycle, namely the anagen-catagen switch in situ.As human pigmentation is tightly coupled to the hair cycle and both human HFs and epidermal melanocytes express clock genes/proteins, this led us to investigate the hypothesis that the molecular clock modulates human pigmentation. By silencing BMAL1 or PER1 in HFs an increase in melanin content (Masson-Fontana) was observed in a hair-cycle independent manner. Furthermore, tyrosinase expression/activity as well as TYRP1 and 2 expression, gp100 protein expression, melanocyte dendricity and the number of HF melanocytes were all significantly increased in BMAL1 and/or PER1-silenced HFs. Mechanistically, BMAL1 knockdown reduced PER1 transcription, and PER1 silencing was found to induce phosphorylation of the master regulator of melanogenesis, MITF, thus stimulating human melanogenesis and melanocyte activity. This provides the first evidence that the peripheral molecular clock influences human pigmentation.Finally, the thyroid hormone (T4) has strong links with peripheral clock activity and has been shown to prolong anagen and increase human HF pigmentation. Moreover, T4 is a commonly prescribed treatment for thyroid disorder. As such, we investigated the hypothesis that T4 influences HF clock gene activity. It was observed that transient T4 treatment reduces the amplitude of clock gene oscillations whilst circadian rhythmicity is maintained. Conversely with longer term treatment clock gene activity was significantly increased compared to a scrambled oligo-control.Here we have demonstrated that the human HF has peripheral molecular clock activity which influences the human hair cycle and pigmentation. Finally we were able to uncover a potential novel target, T4, whose pulsatile administration may potentially be used to treat not only hair growth and pigmentation disorders but may be able to modulate circadian activity in peripheral tissues and treat clock-related disease.

Keyword(s)

Hair follicle; chronobiology; clock; hair cycle; pigmentation; thyroid; thyroxine

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