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Molecular mechanisms and physiological signals underlying daily rhythms in translation

English title Molecular mechanisms and physiological signals underlying daily rhythms in translation
Applicant Gatfield David
Number 179190
Funding scheme Project funding (Div. I-III)
Research institution Centre Intégratif de Génomique Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Molecular Biology
Start/End 01.07.2018 - 31.03.2023
Approved amount 800'000.00
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All Disciplines (2)

Discipline
Molecular Biology
Biochemistry

Keywords (9)

circadian clocks; gene expression regulation; liver; RNA biology; iron metabolism; in vivo recording of gene expression; ribosome profiling; iron response element; translation

Lay Summary (German)

Lead
Zirkadiane Uhren spielen im Menschen und in anderen Säugetieren eine wichtige Rolle bei der tageszeitabhängigen Regulierung einer Vielzahl molekularer und physiologischer Prozesse. Grundlage dieser Rhythmen sind tägliche Genexpressionszyklen, welche verhältnismässig gut auf der Ebene der Transkription - d.h. dem Ablesen der Gene auf der DNA und der Herstellung der Boten-RNA (messenger RNA, mRNA) - verstanden sind (siehe Nobelpreis für Physiologie oder Medizin 2017). In den letzten Jahren haben verschiedene Arbeitsgruppen - inklusive meine Mitarbeiter und ich an der Universität Lausanne - die Beobachtung gemacht, dass auch der Ebene der Translation (d.h. der Biosynthese von Proteinen durch Ribosomen anhand der mRNA) eine wichtige Rolle bei der rhythmischen Genexpression zukommt. Im vorliegenden Projekt werden wir einige paradigmatische Beispiele tageszeitabhängiger Translation experimentell analysieren, insbesondere eine Klasse von Genen, welche wichtig für den Eisenmetabolismus sind.
Lay summary

Die meisten Lebewesen nutzen endogene molekulare Oszillatoren – sogenannte zirkadiane Uhren – um Genexpression, Metabolismus und zahlreiche physiologische Funktionen zu koordinieren und auf den Tag-Nacht-Rhythmus anzupassen. In Säugetieren unterliegen ungefähr 10% des Transkriptoms und des Proteoms einer rhythmischen Kontrolle.

Die geläufigsten molekularen Modelle erklären die Entstehung von Oszillationen über die tageszeitabhängige Aktivität von Transkriptionsfaktoren, die zu einer rhythmischen Synthese von mRNAs führt, welche sich ihrerseits über die ribosomale Proteinbiosynthese in zyklischen Proteinprofilen niederschlägt. Interessanterweise haben mehrere Forschungsarbeiten in den vergangenen Jahren, inklusiver unsere eigenen, gezeigt, dass die Oszillationsdynamik vieler Proteine gar nicht auf rhythmische mRNAs angewiesen ist, sondern direkt auf der Ebene der Translation entsteht.

Im vorliegende Projekt werden wir am Beispiel einiger besonders frappierender Fälle rhythmischer Translation die zugrundeliegenden molekularen Mechanismen experimentell Untersuchen. Der anschaulichste Fall sind eine Klasse von Transkripten, welche für Proteine des Eisenstoffwechels kodieren. In Mäuselebern sind die Mengen dieser Transkripte konstant, jedoch assoziieren sie nur zu spezifischen Tageszeiten mit Ribosomen und führen daher zu oszillierender Proteinbiosynthese. Wir werden untersuchen, was diese Rhythmen erzeugt. Sind sie eine Reaktion auf täglich fluktuierende physiologische Eisenkonzentrationen? Welche Rolle spielt die interne zirkadiane Uhr, und wie wird der Rhythmus doch tägliche Rhythmen von Nahrungsaufnahme beeinflusst?

Es handelt sich bei diesem Projekt um Grundlagenforschung. Aufgrund der Ähnlichkeit zwischen Maus und Mensch und der Bedeutung des zirkadianen Systems für zahlreiche Krankheiten (u.a. Diabetes, Fettleibigkeit, Depression) und andere „Zivilisationserrungenschaften“ (u.a. Jet lag, Schichtarbeit), ist eine medizinische Verwendung der gewonnen Erkenntnisse langfristig zu erwarten. Das Beispiel des Eisenmetabolismus ist hierbei besonders interessant – sogenannte Eisenspeicherkrankheiten könnten durch ein besseres Verständnis der bislang unverstandenen rhythmischen Dimension durchaus neue Therapiemöglichkeiten erfahren.

Direct link to Lay Summary Last update: 04.06.2018

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Circular RNA repertoires are associated with evolutionarily young transposable elements
Gruhl Franziska, Janich Peggy, Kaessmann Henrik, Gatfield David (2021), Circular RNA repertoires are associated with evolutionarily young transposable elements, in eLife, 10, 1.
Transcriptome-wide sites of collided ribosomes reveal principles of translational pausing
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.
Emerging Roles of Translational Control in Circadian Timekeeping
Castelo-Szekely Violeta, Gatfield David (2020), Emerging Roles of Translational Control in Circadian Timekeeping, in Journal of Molecular Biology, 432(12), 3483-3497.
Mammalian RNA Decay Pathways Are Highly Specialized and Widely Linked to Translation
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.
Charting DENR-dependent translation reinitiation uncovers predictive uORF features and links to circadian timekeeping via Clock
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.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EMBO Symposium “The Complex Life of RNA” Poster Investigating the role of NMD in circadian time keeping using a novel genetic Smg6 loss-of-function model. 07.10.2020 Heidelberg, Germany Gatfield David;
9th Swiss Chronobiology Meeting Talk given at a conference "Emerging roles for upstream open reading frames (uORF) translation in the mammalian circadian clock. 03.09.2020 Fribourg, Switzerland Gatfield David;
Lausanne Genomics Days 2020 Talk given at a conference Transcriptome-wide sites of collided ribosomes reveal sequence determinants of translational pausing 10.02.2020 Lausanne, Switzerland Gatfield David;
Swiss RNA Workshop Poster Investigating the role of NMD in circadian gene expression using a novel genetic Smg6 loss-of-function model. 24.01.2020 Bern, Switzerland Gatfield David;
EMBO Workshop: Protein Synthesis and Translational Control Talk given at a conference Transcriptome-wide sites of collided ribosomes reveal sequence determinants of translational pausing 04.09.2019 Heidelberg, Germany Gatfield David;
Gordon Research Conference: Clocks in Model Organisms: Circadian Networks, Physiology and Health Poster Rhythmic translation of iron metabolic genes 23.06.2019 Castelldefels, Spain Gatfield David;
Gordon Research Conference: Clocks in Model Organisms: Circadian Networks, Physiology and Health Talk given at a conference Translational regulation of circadian clocks through upstream open reading frames 23.06.2019 Castelldefels, Spain Gatfield David; Castelo Székely Violeta;
24th Annual Meeting of the RNA Society Individual talk Transcriptome-wide sites of collided ribosomes reveal sequence determinants of translational pausing 11.06.2019 Krakow, Poland Gatfield David;
Swiss RNA Workshop Poster The Role of Upstream Open Reading Frames in the regulation of the circadian Cryptochrome 1 gene 25.03.2019 Bern, Switzerland Gatfield David;
Austrian-Swiss RNA Meeting Poster The Role of Upstream Open Reading Frames in Gatfield the regulation of the circadian Cryptochrome 1 gene 30.01.2019 Hof bei Salzburg, Austria Gatfield David;
Austrian-Swiss RNA Meeting Poster Investigating the role of NMD in circadian gene expression using a novel genetic Smg6 loss-of-function model. 30.01.2019 Hof bei Salzburg, Austria Gatfield David;
Austrian-Swiss RNA Meeting Talk given at a conference Characterization of genome-wide translational pausing events and their functional implications by disome sequencing 30.01.2019 Hof, Austria Gatfield David;
Swiss RNA Workshop Poster Charting DENR-dependent translation reinitiation uncovers predictive uORF features and links to circadian timekeeping via Clock 25.01.2019 Bern, Switzerland Gatfield David; Castelo Székely Violeta;
Swiss RNA Workshop Poster Investigating the role of NMD in circadian gene expression using a novel genetic Smg6 loss-of-function model. 25.01.2019 Bern, Switzerland Gatfield David;
18th Hepatobiliary and Gastrointestinal Research Retreat Talk given at a conference Circadian rhythms in the liver - new regulatory mechanisms acting at the level of mRNA translation 11.01.2019 Les Diablerets, Switzerland Gatfield David;
IMB Workshop: “Molecular Mechanisms of Circadian Clocks” Poster Investigating the role of NMD in circadian gene expression using a novel genetic Smg6 loss-of-function model 15.11.2018 Mainz, Germany Gatfield David;
IMB Workshop: “Molecular Mechanisms of Circadian Clocks” Talk given at a conference A role for upstream open reading frame (uORF) translation in clock regulation 15.11.2018 Mainz, Germany Gatfield David;
IMB Workshop: “Molecular Mechanisms of Circadian Clocks” Poster Translatome-wide, DENR-regulated reinitiation events uncover predictive uORF features and links to circadian timekeeping via Clock regulation 15.11.2018 Mainz, Germany Castelo Székely Violeta; Gatfield David;
EMBO Symposium "The Complex Life of RNA" Poster Genome-wide translational pausing events and their functional implications revealed from the sequencing of disome footprints 03.10.2018 Heidelberg, Germany Gatfield David;
EMBO Symposium "The Complex Life of RNA" Poster The Role of Upstream Open Reading Frames in the regulation of the circadian Cryptochrome 1 gene 03.10.2018 Heidelberg, Germany Gatfield David;
EMBO Symposium "The Complex Life of RNA" Poster Investigating the role of NMD in circadian gene expression using a novel genetic Smg6 loss-of-function model 03.10.2018 Heidelberg, Germany Gatfield David;
EMBO Symposium "The Complex Life of RNA" Poster Translatome-wide, DENR-regulated reinitiation events uncover predictive uORF features and links to circadian timekeeping via Clock regulation 03.10.2018 Heidelberg, Germany Gatfield David; Castelo Székely Violeta;


Awards

Title Year
PRIX DU PROFESSEUR HENRI-A. GUENIN 2020

Associated projects

Number Title Start Funding scheme
157528 Translational control within the circadian clock 01.11.2014 SNSF Professorships
157528 Translational control within the circadian clock 01.11.2014 SNSF Professorships
141735 NCCR RNA & disease: Understanding the role of RNA biology in disease mechanisms (phase I) 01.05.2014 National Centres of Competence in Research (NCCRs)

Abstract

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.
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