A meeting of two chronobiological systems: circadian proteins Period1 and BMAL1 modulate the human hair cycle clock

J Invest Dermatol. 2014 Mar;134(3):610-619. doi: 10.1038/jid.2013.366. Epub 2013 Sep 4.

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.

MeSH terms

  • ARNTL Transcription Factors / genetics*
  • ARNTL Transcription Factors / metabolism
  • Adult
  • Aged
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Circadian Rhythm / physiology*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Female
  • Gene Expression Regulation / physiology
  • Gene Silencing
  • Hair Follicle / cytology
  • Hair Follicle / growth & development
  • Hair Follicle / physiology*
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / physiology
  • Male
  • Middle Aged
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism
  • Organ Culture Techniques
  • Period Circadian Proteins / genetics*
  • Period Circadian Proteins / metabolism
  • Proto-Oncogene Proteins c-myb / genetics
  • Proto-Oncogene Proteins c-myb / metabolism
  • Scalp / cytology
  • Scalp / growth & development
  • Scalp / physiology*

Substances

  • ARNTL Transcription Factors
  • BMAL1 protein, human
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • NR1D1 protein, human
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • PER1 protein, human
  • Period Circadian Proteins
  • Proto-Oncogene Proteins c-myb
  • CLOCK Proteins
  • CLOCK protein, human