Krüppel-like factor 9 is a circadian transcription factor in human epidermis that controls proliferation of keratinocytes

Spörl, Florian; Korge, Sandra; Jürchott, Karsten; Wunderskirchner, Minetta; Schellenberg, Katja; Heins, Sven; Specht, Aljona; Stoll, Claudia; Klemz, Roman; Maier, Bert; Wenck, Horst; Schrader, Annika; Kunz, Dieter; Blatt, Thomas; Kramer, Achim

doi:10.1073/pnas.1118641109

Cited by 134 publications

(135 citation statements)

References 46 publications

(41 reference statements)

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“…KLF15 also coordinates circadian expression of multiple enzyme genes such as Alt and Otc for nitrogen homeostasis rhythms in the liver (46). On the other hand, KLF9 was identified as an important regulator of keratinocyte proliferation through controlling the expression of its target genes in a daytime-dependent manner (47). Collectively, circadian expression of KLF family members contributes to the rhythmic regulation of their target genes and potentially leads to daily variation of physiological functions.…”

Section: Resultsmentioning

confidence: 99%

CLOCK-Controlled Polyphonic Regulation of Circadian Rhythms through Canonical and Noncanonical E-Boxes

Yoshitane

Ozaki

Terajima

et al. 2014

Molecular and Cellular Biology

115

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Many aspects of behavior and physiology, including sleep/ awake cycles and hormone levels, keep a rhythm with about a 24-h period, even under constant conditions without any external time cues (1). Circadian rhythms are generated by a self-sustaining time-measuring system called the circadian clock. In mammals, the hypothalamic suprachiasmatic nucleus (SCN) functions as the master clock, and circadian clocks are also located in peripheral tissues such as the liver (2-5). In individual cells, clock genes and their products form transcriptional/translational feedback loops (6). The basic helix-loop-helix (bHLH)-PAS transcription factors CLOCK and BMAL1 play a role as positive factors in the loops, and the heterodimer of these proteins binds to the CACGTG E-box or related E-box-like sequences to transactivate a wide range of target genes, including Per and Cry (7-10). Translated PER and CRY proteins then bind to the CLOCK-BMAL1 complex, leading to the suppression of E-box-dependent transactivation. This negative-feedback mechanism forms a molecular clock generating circadian rhythms. In addition to the Ebox element, the D-box element and the REV-ERB/ROR-binding element (RRE) form a regulatory network of gene expression, governing coordinately circadian transcriptional oscillations (11,12). The D-box element is activated and repressed by DBP and E4BP4, respectively, while RRE is activated and repressed by RORs and REV-ERBs, respectively.During the circadian cycling of the transcriptional/translational steps, posttranslational modifications, such as phosphorylation, regulate the clock proteins, in terms of activity, stability, localization, and interaction (13). It was reported previously that CLOCK and BMAL1 are phosphorylated in a time-of-day-dependent manner (14)(15)(16)(17). CLOCK phosphorylation at its DNA-binding domain (16, 18) may be important for rhythmic inhibition of the ability of the CLOCK-BMAL1 complex to bind to the E-box element. This is consistent with the observation that the CLOCK-BMAL1 complex rhythmically dissociates from the E-box in the locus of the Dbp gene (19). Here we found in vivo binding sites of CLOCK protein in the mouse liver in a genome-wide manner by chromatin immunoprecipitation-sequencing (ChIP-Seq) analysis. Previous ChIP-Seq studies of circadian clocks confirmed CLOCK-BMAL1 binding to canonical motifs instead of finding all potential binding motifs (20)(21)(22)(23). In this study, significant CLOCK-binding motifs were comprehensively examined by developing a bioinformatics method, MOCCS (motif centrality analysis of ChIP-Seq), which analyzes the frequency distribution of DNA sequences centered at DNA-binding sites found by ChIPSeq analyses. In parallel, all the rhythmic transcripts in the liver were identified by circadian deep-sequencing analysis of poly(A)-tailed RNA and small RNA. Based on these data, we demonstrate the functional importance of rhythmic posttranscriptional regulations, such as microRNA (miRNA)-mediated gene silencing, in dynamic circadian RNA rhythms.

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Section: Resultsmentioning

confidence: 99%

CLOCK-Controlled Polyphonic Regulation of Circadian Rhythms through Canonical and Noncanonical E-Boxes

Yoshitane

Ozaki

Terajima

et al. 2014

Molecular and Cellular Biology

115

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“…In mammals, individual clocks in most cells are synchronized by a brain "master clock" in the suprachiasmatic nucleus of the hypothalamus to orchestrate all rhythmic physiology (2). On a cellular level, circadian physiology extends even to processes such as proliferation (3)(4)(5)(6)(7), apoptosis (8), and DNA damage repair (6,9), which are thought to play important roles in cancer control (8,10).…”

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confidence: 99%

NONO couples the circadian clock to the cell cycle

Kowalska

Ripperger

Hoegger

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

213

210

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Mammalian circadian clocks restrict cell proliferation to defined time windows, but the mechanism and consequences of this interrelationship are not fully understood. Previously we identified the multifunctional nuclear protein NONO as a partner of circadian PE-RIOD (PER) proteins. Here we show that it also conveys circadian gating to the cell cycle, a connection surprisingly important for wound healing in mice. Specifically, although fibroblasts from NONO-deficient mice showed approximately normal circadian cycles, they displayed elevated cell doubling and lower cellular senescence. At a molecular level, NONO bound to the p16-Ink4A cell cycle checkpoint gene and potentiated its circadian activation in a PER proteindependent fashion. Loss of either NONO or PER abolished this activation and circadian expression of p16-Ink4A and eliminated circadian cell cycle gating. In vivo, lack of NONO resulted in defective wound repair. Because wound healing defects were also seen in multiple circadian clock-deficient mouse lines, our results therefore suggest that coupling of the cell cycle to the circadian clock via NONO may be useful to segregate in temporal fashion cell proliferation from tissue organization.keratinocyte | p54nrb | RNA-binding protein | paraspeckle protein T he circadian clock adapts organisms to their daily surroundings both behaviorally and physiologically. In animals, not only are complex behaviors such as sleep and mood governed by this oscillator, but also different body functions such as digestion, circulation, and respiration (1). The basic mechanism of this clock is cell-autonomous in all studied species possessing a circadian clock. In mammals, individual clocks in most cells are synchronized by a brain "master clock" in the suprachiasmatic nucleus of the hypothalamus to orchestrate all rhythmic physiology (2). On a cellular level, circadian physiology extends even to processes such as proliferation (3-7), apoptosis (8), and DNA damage repair (6, 9), which are thought to play important roles in cancer control (8,10).In individual cells, the circadian clock mechanism consists of oscillating feedback loops of transcription of "core" oscillator genes and posttranslational modifications of their protein products that regulate protein stability, activity, and/or localization. For example, in mammals the transcription of periods (Per) and cryptochomes (Cry) are activated by BMAL1:CLOCK heterodimers at cisacting elements called E-boxes, and their protein products form complexes that repress their own transcription (11). We originally identified the RNA-binding protein NONO (also called p54nrb) biochemically as a new member of this circadian transcriptional repressor complex in mice, and mutation of its ortholog NonA in flies resulted in severe attenuation of circadian rhythmicity (12). However, apart from its interaction with this circadian repressor complex, NONO's mechanism of action within the clock remains unknown.The mechanism of the cell cycle has been reviewed extensively elsewhere (13,14). Rathe...

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“…KLF-9) and in their capacity to respond to environmental cues (e.g. TGF-beta) [113,114]. Some of the genes coding for products responsible for kera nocyte prolifera on and differen a on are directly controlled by the circadian clock.…”

Section: Circadian Rhythm Of the Cell Cyclementioning

confidence: 99%

DNA damage and the circadian clock

Chakarov¹,

Petkova²,

Russev³

et al. 2014

Biodiscovery

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The role of the circadian clock has already been demonstrated for virtually all physiological processes, but it was only recently shown that cells were more sensi ve to DNA damage at specific mes of the day; that the peak of synthesis of mRNA and proteins of genes coding for products involved directly or indirectly in DNA repair was differen ally med in different ssues; and that the growth of some types of cancer followed a circadian pa ern. The paper reviews the specifici es of the clockwork mechanism in living cells associated with repair of DNA damage with regards to its role in ageing and carcinogenesis. The role of heritable polymorhisms and soma c muta ons in the risk for development of common diseases (cancer, but also other types of diseases and condi ons, such as obesity and metabolic syndrome), their course and the possible outcomes is reviewed in animal models and in man. The circadian oscilla ons in the levels of major proteins of DNA-damage related signalling and DNA repair are discussed in rela on to differen al mechanisms of defence against genotoxic damage. The paper outlines the modern concept of 'chronotherapy' -that is, an cancer therapy administered at specific mes of the day/ night cycle that could be associated with be er outcomes in some pa ents and analyses the individual variance in the tolerability of chronotherapy vs. maximum-dose an cancer therapy.Cita on: Chakarov S, Petkova R, Russev GCh, Zhelev N. DNA damage and the circadian clock.

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Krüppel-like factor 9 is a circadian transcription factor in human epidermis that controls proliferation of keratinocytes

Cited by 134 publications

References 46 publications

CLOCK-Controlled Polyphonic Regulation of Circadian Rhythms through Canonical and Noncanonical E-Boxes

CLOCK-Controlled Polyphonic Regulation of Circadian Rhythms through Canonical and Noncanonical E-Boxes

NONO couples the circadian clock to the cell cycle

DNA damage and the circadian clock

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