David Gatfield, SNF Professor
|David Gatfield received a Diploma in Biochemistry in 2000 from the University of Tübingen and performed his PhD work at the EMBL in Heidelberg on mechanisms of mRNA transport and degradation in the laboratory of Dr Elisa Izaurralde. In 2004, he joined the group of Dr Ueli Schibler at the University of Geneva for his postdoctoral training, studying circadian rhythms in mice. He joined the CIG as a Swiss National Science Foundation Professor in November 2010.
Keywords: circadian clock, miRNAs, metabolism, post-transcriptional regulation of gene expression
Circadian clocks synchronise biological processes with geophysical time in a variety of organisms, ranging from photosynthetic bacteria to humans. In mammals, such rhythms are evident on many levels, from behaviour (e.g. sleep-wake cycles) and physiology (e.g. blood pressure or digestive activities) down to the molecular level (typically 2-10% of an organ’s transcriptome is rhythmically expressed). Many of these oscillations persist with a near 24-hour period length even under constant conditions and must therefore be driven by an endogenous time-keeping system. Perturbations of circadian rhythms can have serious consequences on human health that go far beyond the discomfort experienced during jet lag or shift work. A multitude of links has thus been established between chronobiology and human disease, including cancer, depressive disorders, or obesity.
According to current models rhythmic transcription constitutes the molecular basis of circadian gene expression. Circadian rhythms are thus generated by feedback loops in clock gene expression involving transcriptional activators (e.g. BMAL1, CLOCK) and repressors (e.g. PERIOD and CRYPTOCHROME proteins). Within this so-called “core clock”, a number of additional proteins and post-translational modifications are known to contribute to the generation of robust oscillations. Circadian transcriptional activities of the core clock are also responsible for controlling the expression of the clock output genes, which drive overt rhythms in physiology.
There is thus little doubt that rhythmic transcription is key to generating rhythmic gene expression. Nevertheless, circadian transcription is not sufficient to explain many observations that have been made, suggesting that important parts of the clock circuitry still remain to be defined. In particular the influence of post-transcriptional regulatory mechanisms on rhythmic gene expression has been largely ignored.
In our lab we therefore wish to explore the contribution of such post-transcriptional mechanisms to circadian gene expression, metabolism and physiology. MicroRNAs (miRNAs) have emerged as a class of translational regulators implicated in numerous processes and these molecules may function in circadian gene expression as well. In this context, we have previously carried out a study on how the hepatocyte-specific miR-122 is embedded in the output system of the liver clock. miRNA-mediated mechanisms in (but not limited to) the circadian clock will remain a particular focus of the lab. For our studies, we use mice and tissue culture cells as experimental systems.
Schneider, K., Köcher, T., Andersin, T., Kurzchalia, T., Schibler, U.*, Gatfield, D.* (2012) CAVIN-3 regulates circadian period length and PER:CRY protein abundance and interactions. EMBO reports 13:1138-44.
Le Martelot, G., Claudel, T., Gatfield, D., Schaad, O., Kornmann, B., Sasso, G.L., Moschetta, A. and Schibler, U. (2009) REV-ERBalpha Participates in Circadian SREBP Signaling and Bile Acid Homeostasis. PLoS Biol 7: e1000181.
Gatfield, D., Le Martelot, G., Vejnar, C.E., Gerlach, D., Schaad, O., Fleury-Olela, F., Ruskeepää, A.-L., Oresic, M., Esau, C.C., Zdobnov, E.M. and Schibler, U. (2009) Integration of microRNA miR-122 in hepatic circadian gene expression. Genes Dev 23: 1313-26.
Gatfield, D. and Schibler, U. (2008) Circadian glucose homeostasis requires compensatory interference between brain and liver clocks. Proc Natl Acad Sci USA 105: 14753-4. (review article)
Asher, G., Gatfield, D., Stratmann, M., Reinke, H., Dibner, C., Kreppel, F., Mostoslavsky, R., Alt, F.W. and Schibler, U. (2008) SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134: 317-28.
Gatfield, D. and Schibler, U. (2007) Proteasomes keep the circadian clock ticking. Science 316: 1135-6. (review article)
Rehwinkel, J., Behm-Ansmant, I., Gatfield, D. and Izaurralde, E. (2005) A crucial role for GW182 and the DCP1:DCP2 decapping complex in miRNA-mediated gene silencing. RNA 11: 1640-7.
Gatfield, D. and Izaurralde, E. (2004) Nonsense-mediated messenger RNA decay is initiated by endonucleolytic cleavage in Drosophila. Nature 429: 575-8.
Palacios, I.M., Gatfield, D., St Johnston, D. and Izaurralde, E. (2004) An eIF4AIII-containing complex required for mRNA localisation and nonsense-mediated mRNA decay. Nature 427: 753-7.
Gatfield, D., Unterholzner, L., Ciccarelli, F.D., Bork, P. and Izaurralde, E. (2003) Nonsense-mediated mRNA decay in Drosophila: at the intersection of the yeast and mammalian pathways. EMBO J 22: 3960-70.