Project acronym 3D-loop
Project Mechanism of homology search and the logic of homologous chromosome pairing in meiosis
Researcher (PI) Aurele PIAZZA
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Starting Grant (StG), LS2, ERC-2019-STG
Summary Homologous recombination (HR) is a conserved DNA double-strand breaks (DSB) repair pathway that uniquely uses an intact DNA molecule as a template. Genome-wide homology search is carried out by a nucleoprotein filament (NPF) assembled on the ssDNA flanking the DSB, and whose product is a “D-loop” joint molecule. Beyond accurate DSB repair, this capacity of HR to spatially associates homologous molecules is also harnessed for homolog pairing in meiosis. The goal of “3D-loop” is to tackle two long lasting conundrums: the fundamental homology search mechanism that achieves accurate and efficient identification of a single homologous donor in the vastness of the genome and nucleus, and how this mechanism is adapted for the purpose of homologs attachment in meiosis.
I overcame the main hurdle to study these core steps of HR by developing a suite of proximity ligation-based methodologies and experimental systems to physically detect joint molecules in yeast cells. It revealed elaborate regulation controlling D-loop dynamics and a novel class of joint molecules. This proposal builds upon these methodologies and findings to first address basic properties of the homology sampling process by the NPF and the role of D-loop dynamics, with the long-term goal to establish a quantitative framework of homology search in mitotic cells (WP1). Second, the meiosis-specific regulation of homology search leading to homolog pairing likely integrates chromosomal-scale information. Genome re-synthesis and engineering approaches will be deployed to (i) achieve a quantitative and dynamic cartography of the cytological and molecular events of meiosis over a large chromosomal region, (ii) probe cis-acting regulations at the chromosomal scale, and (iii) revisit the molecular paradigm for crossover formation (WP2). We expect this project to shed light on the fundamental process of homology search and its involvement in the chromosome pairing phenomenon lying at the basis of sexual reproduction.
Summary
Homologous recombination (HR) is a conserved DNA double-strand breaks (DSB) repair pathway that uniquely uses an intact DNA molecule as a template. Genome-wide homology search is carried out by a nucleoprotein filament (NPF) assembled on the ssDNA flanking the DSB, and whose product is a “D-loop” joint molecule. Beyond accurate DSB repair, this capacity of HR to spatially associates homologous molecules is also harnessed for homolog pairing in meiosis. The goal of “3D-loop” is to tackle two long lasting conundrums: the fundamental homology search mechanism that achieves accurate and efficient identification of a single homologous donor in the vastness of the genome and nucleus, and how this mechanism is adapted for the purpose of homologs attachment in meiosis.
I overcame the main hurdle to study these core steps of HR by developing a suite of proximity ligation-based methodologies and experimental systems to physically detect joint molecules in yeast cells. It revealed elaborate regulation controlling D-loop dynamics and a novel class of joint molecules. This proposal builds upon these methodologies and findings to first address basic properties of the homology sampling process by the NPF and the role of D-loop dynamics, with the long-term goal to establish a quantitative framework of homology search in mitotic cells (WP1). Second, the meiosis-specific regulation of homology search leading to homolog pairing likely integrates chromosomal-scale information. Genome re-synthesis and engineering approaches will be deployed to (i) achieve a quantitative and dynamic cartography of the cytological and molecular events of meiosis over a large chromosomal region, (ii) probe cis-acting regulations at the chromosomal scale, and (iii) revisit the molecular paradigm for crossover formation (WP2). We expect this project to shed light on the fundamental process of homology search and its involvement in the chromosome pairing phenomenon lying at the basis of sexual reproduction.
Max ERC Funding
1 499 779 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym 4D-GenEx
Project Spatio-temporal Organization and Expression of the Genome
Researcher (PI) Antoine COULON
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Starting Grant (StG), LS2, ERC-2017-STG
Summary This project investigates the two-way relationship between spatio-temporal genome organization and coordinated gene regulation, through an approach at the interface between physics, computer science and biology.
In the nucleus, preferred positions are observed from chromosomes to single genes, in relation to normal and pathological cellular states. Evidence indicates a complex spatio-temporal coupling between co-regulated genes: e.g. certain genes cluster spatially when responding to similar factors and transcriptional noise patterns suggest domain-wide mechanisms. Yet, no individual experiment allows probing transcriptional coordination in 4 dimensions (FISH, live locus tracking, Hi-C...). Interpreting such data also critically requires theory (stochastic processes, statistical physics…). A lack of appropriate experimental/analytical approaches is impairing our understanding of the 4D genome.
Our proposal combines cutting-edge single-molecule imaging, signal-theory data analysis and physical modeling to study how genes coordinate in space and time in a single nucleus. Our objectives are to understand (a) competition/recycling of shared resources between genes within subnuclear compartments, (b) how enhancers communicate with genes domain-wide, and (c) the role of local conformational dynamics and supercoiling in gene co-regulation. Our organizing hypothesis is that, by acting on their microenvironment, genes shape their co-expression with other genes.
Building upon my expertise, we will use dual-color MS2/PP7 RNA labeling to visualize for the first time transcription and motion of pairs of hormone-responsive genes in real time. With our innovative signal analysis tools, we will extract spatio-temporal signatures of underlying processes, which we will investigate with stochastic modeling and validate through experimental perturbations. We expect to uncover how the functional organization of the linear genome relates to its physical properties and dynamics in 4D.
Summary
This project investigates the two-way relationship between spatio-temporal genome organization and coordinated gene regulation, through an approach at the interface between physics, computer science and biology.
In the nucleus, preferred positions are observed from chromosomes to single genes, in relation to normal and pathological cellular states. Evidence indicates a complex spatio-temporal coupling between co-regulated genes: e.g. certain genes cluster spatially when responding to similar factors and transcriptional noise patterns suggest domain-wide mechanisms. Yet, no individual experiment allows probing transcriptional coordination in 4 dimensions (FISH, live locus tracking, Hi-C...). Interpreting such data also critically requires theory (stochastic processes, statistical physics…). A lack of appropriate experimental/analytical approaches is impairing our understanding of the 4D genome.
Our proposal combines cutting-edge single-molecule imaging, signal-theory data analysis and physical modeling to study how genes coordinate in space and time in a single nucleus. Our objectives are to understand (a) competition/recycling of shared resources between genes within subnuclear compartments, (b) how enhancers communicate with genes domain-wide, and (c) the role of local conformational dynamics and supercoiling in gene co-regulation. Our organizing hypothesis is that, by acting on their microenvironment, genes shape their co-expression with other genes.
Building upon my expertise, we will use dual-color MS2/PP7 RNA labeling to visualize for the first time transcription and motion of pairs of hormone-responsive genes in real time. With our innovative signal analysis tools, we will extract spatio-temporal signatures of underlying processes, which we will investigate with stochastic modeling and validate through experimental perturbations. We expect to uncover how the functional organization of the linear genome relates to its physical properties and dynamics in 4D.
Max ERC Funding
1 499 750 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym 4DVIDEO
Project 4DVideo: 4D spatio-temporal modeling of real-world events from video streams
Researcher (PI) Marc Pollefeys
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Starting Grant (StG), PE5, ERC-2007-StG
Summary The focus of this project is the development of algorithms that allow one to capture and analyse dynamic events taking place in the real world. For this, we intend to develop smart camera networks that can perform a multitude of observation tasks, ranging from surveillance and tracking to high-fidelity, immersive reconstructions of important dynamic events (i.e. 4D videos). There are many fundamental questions in computer vision associated with these problems. Can the geometric, topologic and photometric properties of the camera network be obtained from live images? What is changing about the environment in which the network is embedded? How much information can be obtained from dynamic events that are observed by the network? What if the camera network consists of a random collection of sensors that happened to observe a particular event (think hand-held cell phone cameras)? Do we need synchronization? Those questions become even more challenging if one considers active camera networks that can adapt to the vision task at hand. How should resources be prioritized for different tasks? Can we derive optimal strategies to control camera parameters such as pan, tilt and zoom, trade-off resolution, frame-rate and bandwidth? More fundamentally, seeing cameras as points that sample incoming light rays and camera networks as a distributed sensor, how does one decide which rays should be sampled? Many of those issues are particularly interesting when we consider time-varying events. Both spatial and temporal resolution are important and heterogeneous frame-rates and resolution can offer advantages. Prior knowledge or information obtained from earlier samples can be used to restrict the possible range of solutions (e.g. smoothness assumption and motion prediction). My goal is to obtain fundamental answers to many of those question based on thorough theoretical analysis combined with practical algorithms that are proven on real applications.
Summary
The focus of this project is the development of algorithms that allow one to capture and analyse dynamic events taking place in the real world. For this, we intend to develop smart camera networks that can perform a multitude of observation tasks, ranging from surveillance and tracking to high-fidelity, immersive reconstructions of important dynamic events (i.e. 4D videos). There are many fundamental questions in computer vision associated with these problems. Can the geometric, topologic and photometric properties of the camera network be obtained from live images? What is changing about the environment in which the network is embedded? How much information can be obtained from dynamic events that are observed by the network? What if the camera network consists of a random collection of sensors that happened to observe a particular event (think hand-held cell phone cameras)? Do we need synchronization? Those questions become even more challenging if one considers active camera networks that can adapt to the vision task at hand. How should resources be prioritized for different tasks? Can we derive optimal strategies to control camera parameters such as pan, tilt and zoom, trade-off resolution, frame-rate and bandwidth? More fundamentally, seeing cameras as points that sample incoming light rays and camera networks as a distributed sensor, how does one decide which rays should be sampled? Many of those issues are particularly interesting when we consider time-varying events. Both spatial and temporal resolution are important and heterogeneous frame-rates and resolution can offer advantages. Prior knowledge or information obtained from earlier samples can be used to restrict the possible range of solutions (e.g. smoothness assumption and motion prediction). My goal is to obtain fundamental answers to many of those question based on thorough theoretical analysis combined with practical algorithms that are proven on real applications.
Max ERC Funding
1 757 422 €
Duration
Start date: 2008-08-01, End date: 2013-11-30
Project acronym AGELESS
Project Comparative genomics / ‘wildlife’ transcriptomics uncovers the mechanisms of halted ageing in mammals
Researcher (PI) Emma Teeling
Host Institution (HI) UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN
Country Ireland
Call Details Starting Grant (StG), LS2, ERC-2012-StG_20111109
Summary "Ageing is the gradual and irreversible breakdown of living systems associated with the advancement of time, which leads to an increase in vulnerability and eventual mortality. Despite recent advances in ageing research, the intrinsic complexity of the ageing process has prevented a full understanding of this process, therefore, ageing remains a grand challenge in contemporary biology. In AGELESS, we will tackle this challenge by uncovering the molecular mechanisms of halted ageing in a unique model system, the bats. Bats are the longest-lived mammals relative to their body size, and defy the ‘rate-of-living’ theories as they use twice as much the energy as other species of considerable size, but live far longer. This suggests that bats have some underlying mechanisms that may explain their exceptional longevity. In AGELESS, we will identify the molecular mechanisms that enable mammals to achieve extraordinary longevity, using state-of-the-art comparative genomic methodologies focused on bats. We will identify, using population transcriptomics and telomere/mtDNA genomics, the molecular changes that occur in an ageing wild population of bats to uncover how bats ‘age’ so slowly compared with other mammals. In silico whole genome analyses, field based ageing transcriptomic data, mtDNA and telomeric studies will be integrated and analysed using a networks approach, to ascertain how these systems interact to halt ageing. For the first time, we will be able to utilize the diversity seen within nature to identify key molecular targets and regions that regulate and control ageing in mammals. AGELESS will provide a deeper understanding of the causal mechanisms of ageing, potentially uncovering the crucial molecular pathways that can be modified to halt, alleviate and perhaps even reverse this process in man."
Summary
"Ageing is the gradual and irreversible breakdown of living systems associated with the advancement of time, which leads to an increase in vulnerability and eventual mortality. Despite recent advances in ageing research, the intrinsic complexity of the ageing process has prevented a full understanding of this process, therefore, ageing remains a grand challenge in contemporary biology. In AGELESS, we will tackle this challenge by uncovering the molecular mechanisms of halted ageing in a unique model system, the bats. Bats are the longest-lived mammals relative to their body size, and defy the ‘rate-of-living’ theories as they use twice as much the energy as other species of considerable size, but live far longer. This suggests that bats have some underlying mechanisms that may explain their exceptional longevity. In AGELESS, we will identify the molecular mechanisms that enable mammals to achieve extraordinary longevity, using state-of-the-art comparative genomic methodologies focused on bats. We will identify, using population transcriptomics and telomere/mtDNA genomics, the molecular changes that occur in an ageing wild population of bats to uncover how bats ‘age’ so slowly compared with other mammals. In silico whole genome analyses, field based ageing transcriptomic data, mtDNA and telomeric studies will be integrated and analysed using a networks approach, to ascertain how these systems interact to halt ageing. For the first time, we will be able to utilize the diversity seen within nature to identify key molecular targets and regions that regulate and control ageing in mammals. AGELESS will provide a deeper understanding of the causal mechanisms of ageing, potentially uncovering the crucial molecular pathways that can be modified to halt, alleviate and perhaps even reverse this process in man."
Max ERC Funding
1 499 768 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym AlCHIMIE
Project From hydrocarbons to original chiral building blocks: new solutions for sustainable & asymmetric CH functionalization of alkanes
Researcher (PI) Joanna WENCEL-DELORD
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Starting Grant (StG), PE5, ERC-2020-STG
Summary Over the last decade, major environmental concerns, a growing worldwide population and an increasing energy demand, combined with the depletion of natural resources, have become crucial issues. Sustainable chemistry-ably to supply society with key chemical products in an eco-compatible manner-has therefore rapidly become an urgent challenge. The AlCHiMIE aims at providing new solutions towards this important defy by developing a set of complementary approaches to convert hydrocarbons, the simplest feedstock, into high value-added chiral alkanes-essential building blocks for medicinal chemistry. Two approaches are thus proposed. First, undirected, metal-free functionalization of hydrocarbons will be achieved by means of regio- and stereo-selective hypervalent bromine-enabled C-H functionalization. This unique reactivity will be attaint by discovering a largely uncharted, yet extremely appealing field of bromanes. The second approach concerns earth-abundant metal-catalyzed C(sp3)-H activation. To obviate the inherent difficulties of this field, namely the low reactivity of alkanes and arduous stereoinduction while using 3d metals, I will develop bifunctional ligands for Co- and Ni-catalyzed C-H activation. In addition to the role of metal coordination, these ligands featuring a second coordinating motif, will enhance the metallation event and will promote the substrate’s activation, thus unlocking the door towards previously inaccessible modes of reactivity. The combination of both strategies will allow unprecedented hydrocarbon valorization by means of undirected, hypervalent bromine-enabled first functionalization followed by exploiting the newly installed coordinating motif to promote directed, asymmetric Co- and Ni-catalyzed C-H activations. Finally, I will also endeavor in establishing new reactivities arising from the application of diversely substituted hypervalent bromines as coupling partners in enantioselective Co- and Ni-catalyzed C-H activations.
Summary
Over the last decade, major environmental concerns, a growing worldwide population and an increasing energy demand, combined with the depletion of natural resources, have become crucial issues. Sustainable chemistry-ably to supply society with key chemical products in an eco-compatible manner-has therefore rapidly become an urgent challenge. The AlCHiMIE aims at providing new solutions towards this important defy by developing a set of complementary approaches to convert hydrocarbons, the simplest feedstock, into high value-added chiral alkanes-essential building blocks for medicinal chemistry. Two approaches are thus proposed. First, undirected, metal-free functionalization of hydrocarbons will be achieved by means of regio- and stereo-selective hypervalent bromine-enabled C-H functionalization. This unique reactivity will be attaint by discovering a largely uncharted, yet extremely appealing field of bromanes. The second approach concerns earth-abundant metal-catalyzed C(sp3)-H activation. To obviate the inherent difficulties of this field, namely the low reactivity of alkanes and arduous stereoinduction while using 3d metals, I will develop bifunctional ligands for Co- and Ni-catalyzed C-H activation. In addition to the role of metal coordination, these ligands featuring a second coordinating motif, will enhance the metallation event and will promote the substrate’s activation, thus unlocking the door towards previously inaccessible modes of reactivity. The combination of both strategies will allow unprecedented hydrocarbon valorization by means of undirected, hypervalent bromine-enabled first functionalization followed by exploiting the newly installed coordinating motif to promote directed, asymmetric Co- and Ni-catalyzed C-H activations. Finally, I will also endeavor in establishing new reactivities arising from the application of diversely substituted hypervalent bromines as coupling partners in enantioselective Co- and Ni-catalyzed C-H activations.
Max ERC Funding
1 499 800 €
Duration
Start date: 2021-02-01, End date: 2026-01-31
Project acronym aLzINK
Project Alzheimer's disease and Zinc: the missing link ?
Researcher (PI) Christelle Sandrine Florence HUREAU-SABATER
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Starting Grant (StG), PE5, ERC-2014-STG
Summary Alzheimer's disease (AD) is one of the most serious diseases mankind is now facing as its social and economical impacts are increasing fastly. AD is very complex and the amyloid-β (Aβ) peptide as well as metallic ions (mainly copper and zinc) have been linked to its aetiology. While the deleterious impact of Cu is widely acknowledged, intervention of Zn is certain but still needs to be figured out.
The main objective of the present proposal, which is strongly anchored in the bio-inorganic chemistry field at interface with spectroscopy and biochemistry, is to design, synthesize and study new drug candidates (ligands L) capable of (i) targeting Cu(II) bound to Aβ within the synaptic cleft, where Zn is co-localized and ultimately to develop Zn-driven Cu(II) removal from Aβ and (ii) disrupting the aberrant Cu(II)-Aβ interactions involved in ROS production and Aβ aggregation, two deleterious events in AD. The drug candidates will thus have high Cu(II) over Zn selectively to preserve the crucial physiological role of Zn in the neurotransmission process. Zn is always underestimated (if not completely neglected) in current therapeutic approaches targeting Cu(II) despite the known interference of Zn with Cu(II) binding.
To reach this objective, it is absolutely necessary to first understand the metal ions trafficking issues in presence of Aβ alone at a molecular level (i.e. without the drug candidates).This includes: (i) determination of Zn binding site to Aβ, impact on Aβ aggregation and cell toxicity, (ii) determination of the mutual influence of Zn and Cu to their coordination to Aβ, impact on Aβ aggregation, ROS production and cell toxicity.
Methods used will span from organic synthesis to studies of neuronal model cells, with a major contribution of a wide panel of spectroscopic techniques including NMR, EPR, mass spectrometry, fluorescence, UV-Vis, circular-dichroism, X-ray absorption spectroscopy...
Summary
Alzheimer's disease (AD) is one of the most serious diseases mankind is now facing as its social and economical impacts are increasing fastly. AD is very complex and the amyloid-β (Aβ) peptide as well as metallic ions (mainly copper and zinc) have been linked to its aetiology. While the deleterious impact of Cu is widely acknowledged, intervention of Zn is certain but still needs to be figured out.
The main objective of the present proposal, which is strongly anchored in the bio-inorganic chemistry field at interface with spectroscopy and biochemistry, is to design, synthesize and study new drug candidates (ligands L) capable of (i) targeting Cu(II) bound to Aβ within the synaptic cleft, where Zn is co-localized and ultimately to develop Zn-driven Cu(II) removal from Aβ and (ii) disrupting the aberrant Cu(II)-Aβ interactions involved in ROS production and Aβ aggregation, two deleterious events in AD. The drug candidates will thus have high Cu(II) over Zn selectively to preserve the crucial physiological role of Zn in the neurotransmission process. Zn is always underestimated (if not completely neglected) in current therapeutic approaches targeting Cu(II) despite the known interference of Zn with Cu(II) binding.
To reach this objective, it is absolutely necessary to first understand the metal ions trafficking issues in presence of Aβ alone at a molecular level (i.e. without the drug candidates).This includes: (i) determination of Zn binding site to Aβ, impact on Aβ aggregation and cell toxicity, (ii) determination of the mutual influence of Zn and Cu to their coordination to Aβ, impact on Aβ aggregation, ROS production and cell toxicity.
Methods used will span from organic synthesis to studies of neuronal model cells, with a major contribution of a wide panel of spectroscopic techniques including NMR, EPR, mass spectrometry, fluorescence, UV-Vis, circular-dichroism, X-ray absorption spectroscopy...
Max ERC Funding
1 499 948 €
Duration
Start date: 2015-03-01, End date: 2021-02-28
Project acronym ANTHROPOID
Project Great ape organoids to reconstruct uniquely human development
Researcher (PI) Jarrett CAMP
Host Institution (HI) INSTITUT FUR MOLEKULARE UND KLINISCHE OPHTHALMOLOGIE BASEL
Country Switzerland
Call Details Starting Grant (StG), LS2, ERC-2018-STG
Summary Humans diverged from our closest living relatives, chimpanzees and other great apes, 6-10 million years ago. Since this divergence, our ancestors acquired genetic changes that enhanced cognition, altered metabolism, and endowed our species with an adaptive capacity to colonize the entire planet and reshape the biosphere. Through genome comparisons between modern humans, Neandertals, chimpanzees and other apes we have identified genetic changes that likely contribute to innovations in human metabolic and cognitive physiology. However, it has been difficult to assess the functional effects of these genetic changes due to the lack of cell culture systems that recapitulate great ape organ complexity. Human and chimpanzee pluripotent stem cells (PSCs) can self-organize into three-dimensional (3D) tissues that recapitulate the morphology, function, and genetic programs controlling organ development. Our vision is to use organoids to study the changes that set modern humans apart from our closest evolutionary relatives as well as all other organisms on the planet. In ANTHROPOID we will generate a great ape developmental cell atlas using cortex, liver, and small intestine organoids. We will use single-cell transcriptomics and chromatin accessibility to identify cell type-specific features of transcriptome divergence at cellular resolution. We will dissect enhancer evolution using single-cell genomic screens and ancestralize human cells to resurrect pre-human cellular phenotypes. ANTHROPOID utilizes quantitative and state-of-the-art methods to explore exciting high-risk questions at multiple branches of the modern human lineage. This project is a ground breaking starting point to replay evolution and tackle the ancient question of what makes us uniquely human?
Summary
Humans diverged from our closest living relatives, chimpanzees and other great apes, 6-10 million years ago. Since this divergence, our ancestors acquired genetic changes that enhanced cognition, altered metabolism, and endowed our species with an adaptive capacity to colonize the entire planet and reshape the biosphere. Through genome comparisons between modern humans, Neandertals, chimpanzees and other apes we have identified genetic changes that likely contribute to innovations in human metabolic and cognitive physiology. However, it has been difficult to assess the functional effects of these genetic changes due to the lack of cell culture systems that recapitulate great ape organ complexity. Human and chimpanzee pluripotent stem cells (PSCs) can self-organize into three-dimensional (3D) tissues that recapitulate the morphology, function, and genetic programs controlling organ development. Our vision is to use organoids to study the changes that set modern humans apart from our closest evolutionary relatives as well as all other organisms on the planet. In ANTHROPOID we will generate a great ape developmental cell atlas using cortex, liver, and small intestine organoids. We will use single-cell transcriptomics and chromatin accessibility to identify cell type-specific features of transcriptome divergence at cellular resolution. We will dissect enhancer evolution using single-cell genomic screens and ancestralize human cells to resurrect pre-human cellular phenotypes. ANTHROPOID utilizes quantitative and state-of-the-art methods to explore exciting high-risk questions at multiple branches of the modern human lineage. This project is a ground breaking starting point to replay evolution and tackle the ancient question of what makes us uniquely human?
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
Project acronym ARCHEIS
Project Understanding the onset and impact of Aquatic Resource Consumption in Human Evolution using novel Isotopic tracerS
Researcher (PI) Klervia Marie Madalen JAOUEN
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Starting Grant (StG), PE10, ERC-2018-STG
Summary The onset of the systematic consumption of marine resources is thought to mark a turning point for the hominin lineage. To date, this onset cannot be traced, since classic isotope markers are not preserved beyond 50 - 100 ky. Aquatic food products are essential in human nutrition as the main source of polyunsaturated fatty acids in hunter-gatherer diets. The exploitation of marine resources is also thought to have reduced human mobility and enhanced social and technological complexification. Systematic aquatic food consumption could well have been a distinctive feature of Homo sapiens species among his fellow hominins, and has been linked to the astonishing leap in human intelligence and conscience. Yet, this hypothesis is challenged by the existence of mollusk and marine mammal bone remains at Neanderthal archeological sites. Recent work demonstrated the sensitivity of Zn isotope composition in bioapatite, the mineral part of bones and teeth, to dietary Zn. By combining classic (C and C/N isotope analyses) and innovative techniques (compound specific C/N and bulk Zn isotope analyses), I will develop a suite of sensitive tracers for shellfish, fish and marine mammal consumption. Shellfish consumption will be investigated by comparing various South American and European prehistoric populations from the Atlantic coast associated to shell-midden and fish-mounds. Marine mammal consumption will be traced using an Inuit population of Arctic Canada and the Wairau Bar population of New Zealand. C/N/Zn isotope compositions of various aquatic products will also be assessed, as well as isotope fractionation during intestinal absorption. I will then use the fully calibrated isotope tools to detect and characterize the onset of marine food exploitation in human history, which will answer the question of its specificity to our species. Neanderthal, early modern humans and possibly other hominin remains from coastal and inland sites will be compared in that purpose.
Summary
The onset of the systematic consumption of marine resources is thought to mark a turning point for the hominin lineage. To date, this onset cannot be traced, since classic isotope markers are not preserved beyond 50 - 100 ky. Aquatic food products are essential in human nutrition as the main source of polyunsaturated fatty acids in hunter-gatherer diets. The exploitation of marine resources is also thought to have reduced human mobility and enhanced social and technological complexification. Systematic aquatic food consumption could well have been a distinctive feature of Homo sapiens species among his fellow hominins, and has been linked to the astonishing leap in human intelligence and conscience. Yet, this hypothesis is challenged by the existence of mollusk and marine mammal bone remains at Neanderthal archeological sites. Recent work demonstrated the sensitivity of Zn isotope composition in bioapatite, the mineral part of bones and teeth, to dietary Zn. By combining classic (C and C/N isotope analyses) and innovative techniques (compound specific C/N and bulk Zn isotope analyses), I will develop a suite of sensitive tracers for shellfish, fish and marine mammal consumption. Shellfish consumption will be investigated by comparing various South American and European prehistoric populations from the Atlantic coast associated to shell-midden and fish-mounds. Marine mammal consumption will be traced using an Inuit population of Arctic Canada and the Wairau Bar population of New Zealand. C/N/Zn isotope compositions of various aquatic products will also be assessed, as well as isotope fractionation during intestinal absorption. I will then use the fully calibrated isotope tools to detect and characterize the onset of marine food exploitation in human history, which will answer the question of its specificity to our species. Neanderthal, early modern humans and possibly other hominin remains from coastal and inland sites will be compared in that purpose.
Max ERC Funding
1 361 991 €
Duration
Start date: 2019-03-01, End date: 2024-08-31
Project acronym BEFINE
Project mechanical BEhavior of Fluid-INduced Earthquakes
Researcher (PI) Marie, Estelle, Solange VIOLAY
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Starting Grant (StG), PE10, ERC-2017-STG
Summary Fluids play an important role in fault zone and in earthquakes generation. Fluid pressure reduces the normal effective stress, lowering the frictional strength of the fault, potentially triggering earthquake ruptures. Fluid injection induced earthquakes (FIE) are direct evidence of the effect of fluid pressure on the fault strength. In addition, natural earthquake sequences are often associated with high fluid pressures at seismogenic depths. Although simple in theory, the mechanisms that govern the nucleation, propagation and recurrence of FIEs are poorly constrained, and our ability to assess the seismic hazard that is associated with natural and induced events remains limited. This project aims to enhance our knowledge of FIE mechanisms over entire seismic cycles through multidisciplinary approaches, including the following:
- Set-up and installation of a new and unique rock friction apparatus that is dedicated to the study of FIEs.
- Low strain rate friction experiments (coupled with electrical conductivity measurements) to investigate the influence of fluids on fault creep and earthquake recurrence.
- Intermediate strain rate friction experiments to investigate the effect of fluids on fault stability during earthquake nucleation.
- High strain rate friction experiments to investigate the effect of fluids on fault weakening during earthquake propagation.
- Post-mortem experimental fault analyses with state-of-art microstructural techniques.
- The theoretical friction law will be calibrated with friction experiments and faulted rock microstructural observations.
These steps will produce fundamental discoveries regarding natural earthquakes and tectonic processes and help scientists understand and eventually manage the occurrence of induced seismicity, an increasingly hot topic in geo-engineering. The sustainable exploitation of geo-resources is a key research and technology challenge at the European scale, with a substantial economical and societal impact.
Summary
Fluids play an important role in fault zone and in earthquakes generation. Fluid pressure reduces the normal effective stress, lowering the frictional strength of the fault, potentially triggering earthquake ruptures. Fluid injection induced earthquakes (FIE) are direct evidence of the effect of fluid pressure on the fault strength. In addition, natural earthquake sequences are often associated with high fluid pressures at seismogenic depths. Although simple in theory, the mechanisms that govern the nucleation, propagation and recurrence of FIEs are poorly constrained, and our ability to assess the seismic hazard that is associated with natural and induced events remains limited. This project aims to enhance our knowledge of FIE mechanisms over entire seismic cycles through multidisciplinary approaches, including the following:
- Set-up and installation of a new and unique rock friction apparatus that is dedicated to the study of FIEs.
- Low strain rate friction experiments (coupled with electrical conductivity measurements) to investigate the influence of fluids on fault creep and earthquake recurrence.
- Intermediate strain rate friction experiments to investigate the effect of fluids on fault stability during earthquake nucleation.
- High strain rate friction experiments to investigate the effect of fluids on fault weakening during earthquake propagation.
- Post-mortem experimental fault analyses with state-of-art microstructural techniques.
- The theoretical friction law will be calibrated with friction experiments and faulted rock microstructural observations.
These steps will produce fundamental discoveries regarding natural earthquakes and tectonic processes and help scientists understand and eventually manage the occurrence of induced seismicity, an increasingly hot topic in geo-engineering. The sustainable exploitation of geo-resources is a key research and technology challenge at the European scale, with a substantial economical and societal impact.
Max ERC Funding
1 982 925 €
Duration
Start date: 2018-03-01, End date: 2023-12-31
Project acronym BioMeTRe
Project Biophysical mechanisms of long-range transcriptional regulation
Researcher (PI) Luca GIORGETTI
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Country Switzerland
Call Details Starting Grant (StG), LS2, ERC-2017-STG
Summary In mammals, transcriptional control of many genes relies on cis-regulatory elements such as enhancers, which are often located tens to hundreds of kilobases away from their cognate promoters. Functional interactions between distal regulatory elements and target promoters require mutual physical proximity, which is linked to the three-dimensional structure of the chromatin fiber. Chromosome conformation capture studies revealed that chromosomes are partitioned into Topologically Associating Domains (TADs), sub-megabase domains of preferential physical interactions of the chromatin fiber. Genetic evidence showed that TAD boundaries restrict the genomic range of enhancer-promoter communication, and that interactions between regulatory sequences within TADs are further fine-tuned by smaller-scale structures. However, the mechanistic details of how physical interactions translate into transcriptional outputs are totally unknown. Here we propose to explore the biophysical mechanisms that link chromosome conformation and long-range transcriptional regulation using molecular biology, genetic engineering, single-cell experiments and physical modeling. We will measure chromosomal interactions in single cells and in time using a novel method that relies on an enzymatic process in vivo. Genetic engineering will be used to establish a cell system that allows quantitative measurement of how enhancer-promoter interactions relate to transcription at the population and single-cell levels, and to test the effects of perturbations without confounding effects. Finally, we will develop physical models of promoter operation in the presence of distal enhancers, which will be used to interpret the experimental data and formulate new testable predictions. With this integrated approach we aim at providing an entirely new layer of description of the general principles underlying transcriptional control, which could establish new paradigms for research in epigenetics and gene regulation.
Summary
In mammals, transcriptional control of many genes relies on cis-regulatory elements such as enhancers, which are often located tens to hundreds of kilobases away from their cognate promoters. Functional interactions between distal regulatory elements and target promoters require mutual physical proximity, which is linked to the three-dimensional structure of the chromatin fiber. Chromosome conformation capture studies revealed that chromosomes are partitioned into Topologically Associating Domains (TADs), sub-megabase domains of preferential physical interactions of the chromatin fiber. Genetic evidence showed that TAD boundaries restrict the genomic range of enhancer-promoter communication, and that interactions between regulatory sequences within TADs are further fine-tuned by smaller-scale structures. However, the mechanistic details of how physical interactions translate into transcriptional outputs are totally unknown. Here we propose to explore the biophysical mechanisms that link chromosome conformation and long-range transcriptional regulation using molecular biology, genetic engineering, single-cell experiments and physical modeling. We will measure chromosomal interactions in single cells and in time using a novel method that relies on an enzymatic process in vivo. Genetic engineering will be used to establish a cell system that allows quantitative measurement of how enhancer-promoter interactions relate to transcription at the population and single-cell levels, and to test the effects of perturbations without confounding effects. Finally, we will develop physical models of promoter operation in the presence of distal enhancers, which will be used to interpret the experimental data and formulate new testable predictions. With this integrated approach we aim at providing an entirely new layer of description of the general principles underlying transcriptional control, which could establish new paradigms for research in epigenetics and gene regulation.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
