Krüppel-like factor 9 is a circadian transcription factor in human epidermis that controls proliferation of keratinocytes.
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, Krüppel-like factor 9 (Klf9), that is substantially up-regulated in a cortisol and differentiation-state-dependent manner. Gain- and loss-of-function 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.
Research and Development, Beiersdorf AG, 20245 Hamburg, Germany.
Florian
F
Spörl
Sandra
S
Korge
Karsten
K
Jürchott
Minetta
M
Wunderskirchner
Katja
K
Schellenberg
Sven
S
Heins
Aljona
A
Specht
Claudia
C
Stoll
Roman
R
Klemz
Bert
B
Maier
Horst
H
Wenck
Annika
A
Schrader
Dieter
D
Kunz
Thomas
T
Blatt
Achim
A
Kramer
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology*; D055106:Genome-Wide Association Study; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000503:physiopathology
D000893:Anti-Inflammatory Agents; C489676:KLF9 protein, human; D051741:Kruppel-Like Transcription Factors; D008156:Luciferases; D006854:Hydrocortisone