Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis

Abstract

The role of the circadian clock in skin and the identity of genes participating in its chronobiology remain largely unknown, leading us to define the circadian transcriptome of mouse skin at two different stages of the hair cycle, telogen and anagen. The circadian transcriptomes of telogen and anagen skin are largely distinct, with the former dominated by genes involved in cell proliferation and metabolism. The expression of many metabolic genes is antiphasic to cell cycle-related genes, the former peaking during the day and the latter at night. Consistently, accumulation of reactive oxygen species, a byproduct of oxidative phosphorylation, and S-phase are antiphasic to each other in telogen skin. Furthermore, the circadian variation in S-phase is controlled by BMAL1 intrinsic to keratinocytes, because keratinocyte-specific deletion of Bmal1 obliterates time-of-day-dependent synchronicity of cell division in the epidermis leading to a constitutively elevated cell proliferation. In agreement with higher cellular susceptibility to UV-induced DNA damage during S-phase, we found that mice are most sensitive to UVB-induced DNA damage in the epidermis at night. Because in the human epidermis maximum numbers of keratinocytes go through S-phase in the late afternoon, we speculate that in humans the circadian clock imposes regulation of epidermal cell proliferation so that skin is at a particularly vulnerable stage during times of maximum UV exposure, thus contributing to the high incidence of human skin cancers.Arntl gene | circadian rhythm | UVB damage | cell cycle T he highly conserved circadian clock regulates organismal adaptation to the light:dark (LD) cycles caused by the rotation of the Earth (1). Located in the suprachiasmatic nucleus of the vertebrate hypothalamus, the central clock is an intrinsic pacemaker with a spontaneous firing rate and a nearly 24-h rhythmic gene expression. This central pacemaker is thought to synchronize peripheral clocks found in the vast majority of tissues and cells. The core circadian clock machinery is composed of the heterodimeric bHLH-PAS transcription factors CLOCK and BMAL1 that bind E-box elements to activate clock-controlled genes, as well as Period (Per1, 2, and 3) and Cryptochrome (Cry1 and 2). PERs and CRYs inhibit CLOCK/BMAL1 activity upon their translocation into the nucleus, thus constituting a negative arm in the circadian feedback loop. CLOCK/ BMAL1 also activate expression of nuclear receptors ROR and REV-ERBα, which in turn respectively activate and inhibit the transcription of Bmal1 and other target genes containing retinoic acid-related orphan receptor response elements.Although the circadian clock is active in most mammalian tissues, the battery of genes under circadian regulation is largely tissue specific (2), suggesting that the circadian clock modulates physiological processes unique to each organ. Here we have focused on the role of the clock within skin, an organ dominated on the one hand by the cycling hair follicles and on the other by the continuously r...

Circadian clock-mediated control of stem cell division and differentiation: beyond night and day

“…Consistent with the possible importance of this regulation, clock protein misexpression and/or a lack of circadian control has been documented in multiple tumor types (Hwang-Verslues et al, 2013; Luo et al, 2012;Zhao et al, 2013) and immortalized cell lines (Yeom et al, 2010). In normal physiology, circadian cell division has been documented in adult hippocampal neurogenesis (BouchardCannon et al, 2013), in intestinal and skin epithelial cell division (Geyfman et al, 2012;Janich et al, 2013;Karpowicz et al, 2013), and in multiple immune cell populations (Fortier et al, 2011;Keller et al, 2009) -essentially anywhere that cell division occurs in adult animals.…”

Overexpression of the Circadian Clock Gene Bmal1 Increases Sensitivity to Oxaliplatin in Colorectal Cancer

“…In addition to its function in controlling biologic rhythm, Bmal1 is closely related to aging, angiocardiopathy, immune disorders, and cancers (8)(9)(10)(11)(12). Recent evidence suggests that Bmal1 is correlated with proliferation and the cell cycle, indicating that Bmal1 may play an important role in tumorigenesis (11,(13)(14)(15). For instance, Bmal1 has been shown to affect the cell cycle and cell proliferation by regulating the p53/p21 signaling pathway (14,15).…”

Timing Matters: Circadian Rhythm in Sepsis, Obstructive Lung Disease, Obstructive Sleep Apnea, and Cancer

“…Disruption of the circadian rhythm is linked with deregulated cell proliferation and the progression of cancer (95,96). A large number of animal studies have shown cancer development in animal models of circadian disruption (94,(97)(98)(99)(100). It was reported that both pancreatic carcinoma and osteosarcoma xenografts grew at a faster rate in animals with suprachiasmatic nuclei lesions (101).…”

“…This notion has been shown in rapidly dividing cells of skin, gut, pancreas, reproductive organs, and bone marrow in humans and animals (89)(90)(91)(92)(93)(94). Disruption of the circadian rhythm is linked with deregulated cell proliferation and the progression of cancer (95,96).…”

“…It was reported that both pancreatic carcinoma and osteosarcoma xenografts grew at a faster rate in animals with suprachiasmatic nuclei lesions (101). In humans, BMAL1/CLOCK, Period 1, and Period 2 are human circadian clock genes found to maintain a rhythmic pattern of cell proliferation and repair of DNA damage (94,(100)(101)(102) (109).…”