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.

Dysregulated circadian rhythm pathway in human osteoarthritis: NR1D1 and BMAL1 suppression alters TGF-β signaling in chondrocytes

“…This observation is in agreement with previous reports using different cell types, as well as mice cartilage 8, 22, 30, 44–47 . We identified lower expression levels of multiple circadian rhythm genes by genome wide RNA sequencing in OA, and bioinformatics analysis revealed that circadian rhythm is the most dysregulated pathway in human OA cartilage.…”

Circadian Clock, Cell Division, and Cancer: From Molecules to Organism

“…Moreover, rhythmic clock gene expression was reported in another constantly remodeling human organ, the hair follicle. Disruption of the clock components Per1 , Bmal1 , or Clock with RNAi significantly prolongs the anagenic phase of intensive epithelial proliferation, suggesting that the clock is required for a normal progression of the hair cycle [74]. Multiple studies provide evidence that the molecular clockwork is important for normal stem cell function in other organs also, such as brain, blood, and intestine [75].…”

The tick tock of odontogenesis

“…Indeed, clock genes modulate the human hair cycle clock independently of the brain suggesting that a peripheral hair clock also exists [44, 45]. Clock genes and their products are also co-expressed with stem cells markers in hair and perturbations of circadian clocks result in changes in hair follicle renewal [46].…”