Circadian clocks govern a wide range of cellular and physiological functions in various organisms. Recent evidence suggests distinct functions of local clocks in peripheral mammalian tissues such as immune responses and cell cycle control. However, studying circadian action in peripheral tissues has been limited so far to mouse models, leaving the implication for human systems widely elusive. In particular, circadian rhythms in human skin, which is naturally exposed to strong daytime-dependent changes in the environment, have not been investigated to date on a molecular level. Here, we present a comprehensive analysis of circadian gene expression in human epidermis. Whole-genome microarray analysis of suction-blister epidermis obtained throughout the day revealed a functional circadian clock in epidermal keratinocytes with hundreds of transcripts regulated in a daytime-dependent manner. Among those, we identified a circadian transcription factor, Krüp-pel-like factor 9 (Klf9), that is substantially up-regulated in a cortisol and differentiation-state-dependent manner. Gain-and loss-offunction experiments showed strong antiproliferative effects of Klf9. Putative Klf9 target genes include proliferation/differentiation markers that also show circadian expression in vivo, suggesting that Klf9 affects keratinocyte proliferation/differentiation by controlling the expression of target genes in a daytime-dependent manner.glucocorticoids | skin cancer B iological rhythms regulate cellular and physiological processes ranging from milliseconds to years. A well-studied timing system is the circadian (∼24-h) clockwork that allows organisms to anticipate diurnal variations in environmental conditions such as light, food availability, oxidative stress, pathogen exposure, or temperature. In mammals, the central circadian pacemaker resides in the suprachiasmatic nucleus (SCN), located in the anterior hypothalamus. Oscillations of SCN neurons are cell-autonomous, self-sustained, and synchronized to external time cues (Zeitgebers) such as light (1). The SCN, in turn, synchronizes peripheral clocks by systemic time cues such as neuronal input, hormonal signaling (e.g., cortisol), body temperature, and possibly many others (2). Interestingly, most cells in peripheral tissues also possess cell-autonomous clockworks with a similar molecular makeup to SCN neurons. These peripheral clocks are thought to generate or amplify daytime-dependent physiological and metabolic functions in a tissue-specific manner by circadian regulation of clock-controlled genes (3, 4).On a molecular level, circadian oscillation is generated by interlocked transcriptional-translational feedback loops. The transcription factor dimer CLOCK/BMAL1 drives expression of target genes such as Periods (Per1-3) and Cryptochromes (Cry1-2) by binding to E-box elements in their promoters. The negative feedback is formed by PER/CRY protein complexes that shuttle back into the nucleus, where they block CLOCK/BMAL1-mediated transactivation, thereby inhibiting their own transcr...