circadian clocks; gene expression regulation; liver; RNA biology; iron metabolism; in vivo recording of gene expression; ribosome profiling; iron response element; translation
Gruhl Franziska, Janich Peggy, Kaessmann Henrik, Gatfield David (2021), Circular RNA repertoires are associated with evolutionarily young transposable elements, in eLife
, 10, 1.
Arpat Alaaddin Bulak, Liechti Angélica, De Matos Mara, Dreos René, Janich Peggy, Gatfield David (2020), Transcriptome-wide sites of collided ribosomes reveal principles of translational pausing, in Genome Research
, 30(7), 985-999.
Castelo-Szekely Violeta, Gatfield David (2020), Emerging Roles of Translational Control in Circadian Timekeeping, in Journal of Molecular Biology
, 432(12), 3483-3497.
Tuck Alex Charles, Rankova Aneliya, Arpat Alaaddin Bulak, Liechti Luz Angelica, Hess Daniel, Iesmantavicius Vytautas, Castelo-Szekely Violeta, Gatfield David, Bühler Marc (2020), Mammalian RNA Decay Pathways Are Highly Specialized and Widely Linked to Translation, in Molecular Cell
, 77, 1-15.
Castelo-Szekely Violeta, De Matos Mara, Tusup Marina, Pascolo Steve, Ule Jernej, Gatfield David (2019), Charting DENR-dependent translation reinitiation uncovers predictive uORF features and links to circadian timekeeping via Clock, in Nucleic Acids Research
, 47(10), 5193-5209.
Previous work, including from my lab, has demonstrated that in organs such as the liver, a significant proportion of gene expression rhythms is engendered post-transcriptionally, rather than by the better known, transcriptionally driven mechanisms. However, the precise molecular underpinnings and physiological pathways that drive such post-transcriptional oscillations are poorly understood. Here, I propose a project that will provide mechanistic insights into how protein biosynthesis (translation) is regulated in a rhythmic fashion. We shall identify the implicated upstream physiological signals, the mRNA sequence elements, and trans-acting players. Of note, such an understanding is important to delineate the molecular basis of the numerous functions that gene/protein expression oscillations have in the organism, namely to temporally organize metabolism, physiology and behaviour over the course of the day - functions that are typically attributed to the activity of an internal (circadian) clock.We have recently mapped the mouse liver translatome, i.e. the actively translated mRNAs, transcriptome-wide and around-the-clock using the technique ribosome profiling. We identified almost 150 genes whose transcript abundances were invariable across the day, but that showed robust daily rhythms in translation and (as demonstrated for several paradigmatic cases) in protein levels. Based on our genome-wide approaches we have now formulated several hypotheses and questions regarding the underlying molecular mechanisms, such as: To what extent do the identified cases of translational rhythms require functional circadian clocks in the organism and/or in the organ? Are they driven by other cues, for example systemic signals related to feeding/fasting cycles? Precisely which rhythmic signals, metabolites, molecular protein players, and RNA sequence elements are involved, and do they offer possibilities to manipulate rhythmicity in vivo? In our project, we will showcase one specific paradigm, i.e. the group of iron response element (IRE)-containing transcripts. IREs are textbook examples for translation regulatory RNA elements with clinical relevance (iron storage diseases), whose rhythmic activity had gone unnoticed prior to our study. Moreover, we are interested in a small number of other rhythmically translated genes for which very little is known in terms of function and mechanism. To achieve our aims, we plan to use innovative in vivo recording technology in mice, together with biochemical methods.Beyond investigating important questions in chronobiology, it is the ambition of our project to use the circadian system as a paradigm for naturally occurring differential gene expression and, in the broadest sense, of how genetically wired gene expression information (the local circadian clock) and external cues (e.g. feeding, metabolites) are integrated at the translational level to give rise to the final, physiologically relevant protein biosynthetic output. We thus hope to uncover fundamental principles of translational regulation and its dynamics that are of interest to the wider gene expression and physiology communities.