Circadian Clock Regulation in Skin

Summary

Principal Investigator: Bogi Andersen
Abstract: PROJECT SUMMARY/ABSTRACT Using genetic mouse models, we found that the circadian clock within keratinocytes is required for the time-of- day dependent variation in interfollicular epidermal cell proliferation, which seems to be coordinated with circadian clock-regulated metabolism. Thus, we find that the expression of genes involved in oxidative phosphorylation and reactive oxygen species (ROS) levels are antiphasic to S-phase, and that the circadian variation in ROS levels depends on core clock regulator BMAL1. Furthermore, we found that mice are more sensitive to UVB-induced DNA epidermal damage during the night (when the highest numbers of epidermal cells go through S-phase) than the day. Based on this work we propose this central hypothesis: The circadian clock coordinates the timing of metabolism and cell proliferation in the epidermis, imposing separation between the times of maximum ROS generation and S-phase. While this temporal regulatory arrangement minimizes DNA mutations from endogenous ROS, it causes circadian variation in the sensitivity to UVR-mediated DNA damage in the epidermis. The implication is that diurnal humans may be especially sensitive to UVR-mediated DNA damage during the day, the time of maximum UV exposure. We plan to pursue these ideas in three Specific Aims: (1) To understand the relationships between the circadian clock, metabolism, and cell proliferation at a single cell resolution in the interfollicular epidermis. We will map the cell cycle stage controlled by BMAL1 and use innovative imaging methods to define the relationship between clock output, metabolism, and cell cycle progression at a single cell level within the basal cell layer of the epidermis. We will also test the hypothesis that different feeding schedules can change timing of metabolism and cell proliferation in the epidermis. (2) To identify time-of-day dependent BMAL1 target genes in the interfollicular epidermis. We will use chromatin immunoprecipitation sequencing (ChIP-seq) and chromosome conformation capture (3C) assays to test the hypothesis that BMAL1 directly and indirectly regulates key metabolism and cell cycle genes within the living epidermis. (3) To determine whether core circadian clock genes are required for time-of-day dependent differences in UVR-induced skin carcinogenesis. We will characterize the role of the central clock regulators in the UVB DNA damage response in human keratinocytes and take advantage of a UV-induced mouse carcinogenesis model to test the hypothesis that time-of-day-dependent variation in skin carcinogenesis depends on circadian clock mechanisms. The work is significant because it reveals the relationship between the clock, metabolism, cell proliferation and cancer in a rapidly proliferating epithelium, because it suggests that circadian regulation may contribute to the high incidence of skin cancer in humans, and because it may ultimately lead to ideas about how metabolism can be modulated in proliferating epithelia to decrease carcinogenesis and tissue aging. The work is innovative because it suggests a new role for the circadian clock in imposing temporal separation of metabolism and DNA synthesis in epidermal progenitors.
Funding Period: 2008-07-01 - 2018-08-31
more information: NIH RePORT

Top Publications

  1. pmc Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis
    Mikhail Geyfman
    Department of Biological Chemistry, University of California, Irvine, CA 92697, USA
    Proc Natl Acad Sci U S A 109:11758-63. 2012
  2. pmc The estrogen-responsive Agr2 gene regulates mammary epithelial proliferation and facilitates lobuloalveolar development
    Suman Verma
    Department of Medicine, University of California, Irvine, USA
    Dev Biol 369:249-60. 2012

Research Grants

Detail Information

Publications3

  1. pmc Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis
    Mikhail Geyfman
    Department of Biological Chemistry, University of California, Irvine, CA 92697, USA
    Proc Natl Acad Sci U S A 109:11758-63. 2012
    ....
  2. pmc The estrogen-responsive Agr2 gene regulates mammary epithelial proliferation and facilitates lobuloalveolar development
    Suman Verma
    Department of Medicine, University of California, Irvine, USA
    Dev Biol 369:249-60. 2012
    ..The pro-proliferative effects of Agr2 may explain its actions in early tumorigenesis...

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Role of exogenous melatonin in skin biology
    Andrzej T Slominski; Fiscal Year: 2013
    ..g. vitiligo or hyperpigmentation), proliferative processes (including precancerous states, epidermal cancer or even melanoma), UVB-induced pathology, inflammatory dermatoses and skin aging. ..
  3. Elafin Therapy for Lung Diseases
    Marlene Rabinovitch; Fiscal Year: 2013
    ..The Administrative Core facilitates exchange of information and postdoctoral training in Lung Translational Medicine, and facilitates our strategy to move elafin into clinical trial in the next cycle. ..
  4. Role of the circadian clock in melanocyte biology and UV-induced melanomagenesis
    Shobhan Gaddameedhi; Fiscal Year: 2013
    ..The information obtained will be used to test whether circadian effects on melanocyte biology can be exploited to prevent UVR-induced melanomagenesis. ..
  5. MicroRNA-mediated Regulation in Mammalian Skin
    Rui Yi; Fiscal Year: 2013
    ..The knowledge gained from these studies under normal development condition will also pave the way to investigate miRNA's roles in human diseases e.g. skin cancers where regulatory networks go awry. ..
  6. Mouse nude locus and skin development
    Janice L Brissette; Fiscal Year: 2013
    ..Thus, by identifying Foxn1 effectors, the project should provide insight into disorders associated with the abnormal growth, differentiation, or activity of melanocytes and epithelial cells. ..
  7. Targeting p53-Dependent Repigmentation in Vitiligo
    TAMARA G TERZIAN; Fiscal Year: 2013
    ....
  8. Mechanisms of Genetic Reversion in Ichthyosis With Confetti
    Keith A Choate; Fiscal Year: 2013
    ....
  9. Characterization of persistent hyperemic foci and their role in photocarcinogenes
    Raymond L Konger; Fiscal Year: 2013
    ....
  10. Mechanisms of photocarcinogenesis in geriatric skin
    Jeffrey B Travers; Fiscal Year: 2013
    ..Furthermore, we will continue to evaluate the utility of prophylactic therapies that can prevent the occurrence of aging-associated photocarcinogenesis. ..
  11. Etiological Studies of Gastric Carcinoma
    PELAYO NONE CORREA; Fiscal Year: 2013
    ..Core A provides histopathology services for all projects. Core B deals with all administrative matters and data management. Core C coordinates all field work in Colombia. ..
  12. Mechanisms of Telomere Resistance to DNA Lesion Removal
    PATRICIA LYNN OPRESKO; Fiscal Year: 2013
    ....
  13. The role of TC-PTP in skin carcinogenesis
    Dae Joon Kim; Fiscal Year: 2013
    ....
  14. REGULATION OF EPIDERMAL DEVELOPMENT AND DIFFERENTIATION
    Elaine Fuchs; Fiscal Year: 2013
    ....
  15. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  16. Role of Desmosomal Adhesion in Carcinogenesis
    MY GEORGIA MAHONEY; Fiscal Year: 2013
    ..Determining the molecular mechanisms by which desmoglein 2 affects tumor growth and development has the potential of identifying new targets for therapeutic cancer treatments. ..
  17. Role of p53 homologs in DNA repair in human keratinocytes
    Dennis H Oh; Fiscal Year: 2013
    ....
  18. Prevention of UV-carcinogenesis through DNA repair-dependent immunomodulation
    Hui Xu; Fiscal Year: 2013
    ..The generation of new knowledge will provide novel insights into the mechanisms by which silymarin can either correct, or compensate for, the UV-induced damage that triggers or promotes photocarcinogenesis. ..
  19. The Role of Protein Kinase D in Epidermal Tumorigenesis
    Wendy B Bollag; Fiscal Year: 2013
    ..Evidence concerning the role of PKD in the keratinocyte response to UVB may be important for predicting possible sun sensitivity in patients undergoing systemic chemotherapy with PKD inhibitors. ..
  20. mTOR signaling in keratinocyte UVB response
    THERESA DIANE CARR; Fiscal Year: 2013
    ..mTOR is activated by sun exposure, and we believe mTOR contributes to the development of skin cancer. Our research will investigate mTOR as a possible target for the prevention of skin cancer. ..
  21. Apigenin restores TSP-1 expression in UVB-irradiated keratinocytes
    Jill C Pelling; Fiscal Year: 2013
    ..Identifying TSP-1 as a key target of apigenin and demonstrating its important role in chemoprevention by Api will provide a new target and rationale for improved treatment and prevention strategies for NMSC. ..
  22. Aldehyde dehydrogenase: A novel regulator of melanin biogenesis
    Anand K Ganesan; Fiscal Year: 2013
    ..In this proposal, we characterize putative regulators (Aldhl and Aldh9) of UV induced tanning and determine whether these genes regulate tanning in human skin models. ..
  23. Prevention of photocarcinogenesis by dietary immunomodulation
    Santosh Kumar Katiyar; Fiscal Year: 2013
    ..The development of more effective preventive approaches, such as dietary GSPs that exhibit no toxicity in mice, requires an improved understanding of the mechanisms by which they prevent UVB-induced carcinogenesis. ..
  24. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
    ..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..
  25. Regulation of Nucleotide Excision Repair by Proteolysis
    Pengbo Zhou; Fiscal Year: 2013
    ..abstract_text> ..
  26. Mechanisms of UVA-induced skin cancer
    Yu Ying He; Fiscal Year: 2013
    ..Understanding how PTEN is regulated when we are exposed to UVA and its consequences in skin cancer will improve our ability to reduce the disease burden of this most common cancer. ..
  27. DNA Excision Repair and DNA Damage Checkpoints
    Aziz Sancar; Fiscal Year: 2013
    ..Understanding this DNA damage signaling pathway should facilitate the design of novel chemotherapeutic approaches to treat cancer. ..
  28. Growth/differentiation control of keratinocytes by ROR alpha
    Jun Dai; Fiscal Year: 2013
    ..Pharmacologically, we will test whether treatment with a ROR1 specific agonist (CGP 52608) can affect chemical- induced and/or xenograft tumor formation. ) ..
  29. Importance of Gender in the Chemoprevention of UV induced Skin Cancer
    Tatiana M Oberyszyn; Fiscal Year: 2013
    ..A clearer understanding of the differences in the skin of males and females will ultimately allow for the development of more appropriately targeted prevention and treatment strategies for this most common form of cancer in humans. ..