Research in our group combines two scientific themes, RNA biology and circadian clocks.
A considerable proportion of mammalian gene expression undergoes rhythmic oscillations driven by circadian clocks. While it has been commonly thought that the majority of mRNA and protein rhythms is generated by cyclic transcription, there is accumulating evidence that post-transcriptional mechanisms make important contributions as well. Using mouse organs such as the liver and tissue culture cells as model systems, we investigate how mechanisms acting at the mRNA level participate in shaping the rhythmic transcriptome and proteome, and what consequences such regulation has for metabolism, physiology and behaviour.
In the past, one specific focus has been on the activity of microRNAs in the context of circadian gene expression. Moreover, we have initiated research lines that aim to comprehensively investigate the regulation of translation around-the-clock, and to discover RNA-binding proteins (RBPs) that function as core clock regulators. These may serve as entry points into the discovery of novel regulatory mechanisms occurring at any level of RNA metabolism from transcription to splicing, nuclear export, translation and degradation.
In summary, in the broadest sense we are interested in the question of how post-transcriptional regulatory mechanisms contribute to gene expression in complex physiological situations. Circadian rhythms can be considered an excellent paradigm for such a process that is amenable to studies from the biochemical up to the behavioural level since circadian clocks are both cell-autonomous and under systemic control. In addition to offering very exciting biological questions in its own right, the circadian field may thus ideally serve to uncover general principles of gene expression regulation.
Du NH, Arpat AB, De Matos M, Gatfield D. (2014) MicroRNAs shape circadian hepatic gene expression on a transcriptome-wide scale. eLife 3:02510.
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.
Kojima S, Gatfield D, Esau CC, Green CB. (2010) MicroRNA-122 Modulates the Rhythmic Expression Profile of the Circadian Deadenylase Nocturnin in Mouse Liver. PLoS One 5:e11264.
Le Martelot G, Claudel T, Gatfield D, Schaad O, Kornmann B, Sasso GL, Moschetta A, Schibler U. (2009) REV-ERBalpha Participates in Circadian SREBP Signaling and Bile Acid Homeostasis. PLoS Biology 7:e1000181.
Gatfield D, Le Martelot G, Vejnar CE, Gerlach D, Schaad O, Fleury-Olela F, Ruskeepää AL, Oresic M, Esau CC, Zdobnov EM, Schibler U. (2009) Integration of microRNA miR-122 in hepatic circadian gene expression. Genes&Development 23:1313-26.
Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, Kreppel F, Mostoslavsky R, Alt FW, Schibler U. (2008) SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134:317-28.
Gatfield D, Izaurralde E. (2004) Nonsense-mediated messenger RNA decay is initiated by endonucleolytic cleavage in Drosophila. Nature 429:575-8.
Gatfield D, Unterholzner L, Ciccarelli FD, Bork P, Izaurralde E. (2003) Nonsense-mediated mRNA decay in Drosophila: at the intersection of the yeast and mammalian pathways. EMBO Journal 22:3960-70.