Two chronobiological systems meet: Clock genes modulate cyclic organ regeneration of the human hair follicle

  • Yusur Al-Nuaimi, 1) Integrative Systems Biology and 2) Dermatology Research, Epidermal Sciences. The University of Manchester, United Kingdom
  • Jennifer Klatte, Department of Dermatology, University of Lübeck,, Germany
  • Michael Philpott, Centre for Cutaneous Research, QMW College, London, United Kingdom
  • Balázs Tóth, Department of Physiology and Cell Physiology, University of Debrecen, Hungary, Hungary
  • Stephan Tiede, Department of Dermatology, University of Lübeck,, Germany
  • Rachel Watson, Dermatology Research, Epidermal Sciences, School of Translational Medicine, University of Manchester, UK, United Kingdom
  • Tamás Biro, Department of Physiology and Cell Physiology, University of Debrecen, Hungary
  • Prof Ralf Paus, University of Luebeck, Germany & University of Manchester, United Kingdom, United Kingdom

Objective: The molecular controls of hair follicle (HF) cycling remain unknown, but are of the utmost clinical importance. Since clock genes can also regulate supra-circadian events (including the murine hair cycle), we have explored their role in human hair cycle control.
Methods: Microdisssected, organ-cultured human scalp HFs were harvested during one defined time window. Clock gene and protein expression was compared between anagen VI and (spontaneously developed) catagen HFs by Q-PCR and/or immunohistology. Gene knock-down using siRNA for Clock and Period1 was performed and further HFs were treated with thyrotropin-releasing hormone (TRH) (a potent regulator of clock genes and a recently identified stimulator of human HF growth).
Results: Human HFs differentially transcribed Clock, Bmal1, Period1, Cry1 and Cry2 in a hair-cycle dependent manner. For example, anagen VI HFs showed increased levels of Clock, Cry2 mRNA and Period1 compared to catagen HFs. PERIOD1 protein was maximally expressed in late catagen HFs. siRNA transfection successfully knocked-down Clock and Period1 mRNA transcription in organ-cultured human HFs and altered HF cycling and/or pigmentation. For example, Period 1 knock-down greatly retarded catagen development, and Clock siRNA increased hair matrix keratinocyte proliferation. Period1 and Clock knock-down increased the HF melanin content and altered the expression of genes implicated in the anagen-catagen switch. Finally, the catagen-inhibitory neuropeptide hormone,TRH up-regulated Clock, Cry1, Cry2 and Bmal1 mRNA while it decreased Period1 gene and protein expression.
Conclusions: This is the first report of significant, differential, hair cycle-dependent expression of clock genes and proteins in human HFs. We also provide the first functional evidence that clock genes are indeed involved in human hair cycle control, are regulated by TRH. This offers important novel insights into HF chronobiology and identifies specific clock genes as promising molecular targets for clinical intervention in patients with hair growth disorders.