Project acronym 3MC
Project 3D Model Catalysts to explore new routes to sustainable fuels
Researcher (PI) Petra Elisabeth De jongh
Host Institution (HI) UNIVERSITEIT UTRECHT
Country Netherlands
Call Details Consolidator Grant (CoG), PE4, ERC-2014-CoG
Summary Currently fuels, plastics, and drugs are predominantly manufactured from oil. A transition towards renewable resources critically depends on new catalysts, for instance to convert small molecules (such as solar or biomass derived hydrogen, carbon monoxide, water and carbon dioxide) into more complex ones (such as oxygenates, containing oxygen atoms in their structure). Catalyst development now often depends on trial and error rather than rational design, as the heterogeneity of these composite systems hampers detailed understanding of the role of each of the components.
I propose 3D model catalysts as a novel enabling tool to overcome this problem. Their well-defined nature allows unprecedented precision in the variation of structural parameters (morphology, spatial distribution) of the individual components, while at the same time they mimic real catalysts closely enough to allow testing under industrially relevant conditions. Using this approach I will address fundamental questions, such as:
* What are the mechanisms (structural, electronic, chemical) by which non-metal promoters influence the functionality of copper-based catalysts?
* Which nanoalloys can be formed, how does their composition influence the surface active sites and catalytic functionality under reaction conditions?
* Which size and interface effects occur, and how can we use them to tune the actitivity and selectivity towards desired products?
Our 3D model catalysts will be assembled from ordered mesoporous silica and carbon support materials and Cu-based promoted and bimetallic nanoparticles. The combination with high resolution characterization and testing under realistic conditions allows detailed insight into the role of the different components; critical for the rational design of novel catalysts for a future more sustainable production of chemicals and fuels from renewable resources.
Summary
Currently fuels, plastics, and drugs are predominantly manufactured from oil. A transition towards renewable resources critically depends on new catalysts, for instance to convert small molecules (such as solar or biomass derived hydrogen, carbon monoxide, water and carbon dioxide) into more complex ones (such as oxygenates, containing oxygen atoms in their structure). Catalyst development now often depends on trial and error rather than rational design, as the heterogeneity of these composite systems hampers detailed understanding of the role of each of the components.
I propose 3D model catalysts as a novel enabling tool to overcome this problem. Their well-defined nature allows unprecedented precision in the variation of structural parameters (morphology, spatial distribution) of the individual components, while at the same time they mimic real catalysts closely enough to allow testing under industrially relevant conditions. Using this approach I will address fundamental questions, such as:
* What are the mechanisms (structural, electronic, chemical) by which non-metal promoters influence the functionality of copper-based catalysts?
* Which nanoalloys can be formed, how does their composition influence the surface active sites and catalytic functionality under reaction conditions?
* Which size and interface effects occur, and how can we use them to tune the actitivity and selectivity towards desired products?
Our 3D model catalysts will be assembled from ordered mesoporous silica and carbon support materials and Cu-based promoted and bimetallic nanoparticles. The combination with high resolution characterization and testing under realistic conditions allows detailed insight into the role of the different components; critical for the rational design of novel catalysts for a future more sustainable production of chemicals and fuels from renewable resources.
Max ERC Funding
1 999 625 €
Duration
Start date: 2015-09-01, End date: 2020-11-30
Project acronym ApeGenomeDiversity
Project Great ape genome variation now and then: current diversity and genomic relics of extinct primates
Researcher (PI) Tomas MARQUES BONET
Host Institution (HI) UNIVERSIDAD POMPEU FABRA
Country Spain
Call Details Consolidator Grant (CoG), LS2, ERC-2019-COG
Summary In our quest to fully understand the processes that shape the genomic variation of species, describing variation of the past is a fundamental objective. However, the origins and the extent of great ape variation, the genomic description of extinct primate species and the genomic footprints of introgression events all remain unknown. Even today, and in contraposition to human evolutionary biology, the almost null presence of ancient great ape samples has precluded a comprehensive exploration of such diversity.
Here, I present two approaches that will expose great ape diversity throughout time and will allow me to compare the genomic impact of introgression events across lineages. First, I would like to take advantage of ancient ape samples that will provide us with a direct view of the genomes of extinct populations. Second, I would like to exploit current and recent diversity to indirectly access the parts of extinct ape genomes that became hybridized with current species in the past. For the latter, we will analyse hundreds of non-invasive samples taken from present-day great apes as well as historical specimens. Altogether, this information will enable me to decipher novel genomes that until now have been lost in time. In this way, I will be able to properly understand the origins and dynamics of genomic variants and to study how admixture has contributed to today´s adaptive landscape.
By completing this proposal and performing analogies to the human lineage, fundamental insights will be revealed about (i) the spatial-temporal history of our closest species and (ii) the functional consequences of introgressed events. On top of that, these results will help to annotate functional consequences of novel mutations in the human genome. In so doing, a fundamental insight will be provided into the evolutionary history of these regions and into human mutations with multiple repercussions in the understanding of evolution and human biology.
Summary
In our quest to fully understand the processes that shape the genomic variation of species, describing variation of the past is a fundamental objective. However, the origins and the extent of great ape variation, the genomic description of extinct primate species and the genomic footprints of introgression events all remain unknown. Even today, and in contraposition to human evolutionary biology, the almost null presence of ancient great ape samples has precluded a comprehensive exploration of such diversity.
Here, I present two approaches that will expose great ape diversity throughout time and will allow me to compare the genomic impact of introgression events across lineages. First, I would like to take advantage of ancient ape samples that will provide us with a direct view of the genomes of extinct populations. Second, I would like to exploit current and recent diversity to indirectly access the parts of extinct ape genomes that became hybridized with current species in the past. For the latter, we will analyse hundreds of non-invasive samples taken from present-day great apes as well as historical specimens. Altogether, this information will enable me to decipher novel genomes that until now have been lost in time. In this way, I will be able to properly understand the origins and dynamics of genomic variants and to study how admixture has contributed to today´s adaptive landscape.
By completing this proposal and performing analogies to the human lineage, fundamental insights will be revealed about (i) the spatial-temporal history of our closest species and (ii) the functional consequences of introgressed events. On top of that, these results will help to annotate functional consequences of novel mutations in the human genome. In so doing, a fundamental insight will be provided into the evolutionary history of these regions and into human mutations with multiple repercussions in the understanding of evolution and human biology.
Max ERC Funding
1 896 875 €
Duration
Start date: 2020-06-01, End date: 2025-05-31
Project acronym ATTOLIQ
Project Attosecond X-ray spectroscopy of liquids
Researcher (PI) Hans Jakob WoeRNER
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Consolidator Grant (CoG), PE4, ERC-2017-COG
Summary Charge and energy transfer are the key steps underlying most chemical reactions and biological transformations. The purely electronic dynamics that control such processes take place on attosecond time scales. A complete understanding of these dynamics on the electronic level therefore calls for new experimental methods with attosecond resolution that are applicable to aqueous environments. We propose to combine the element sensitivity of X-ray spectroscopy with attosecond temporal resolution and ultrathin liquid microjets to study electronic dynamics of relevance to chemical, biological and photovoltaic processes. We will build on our recent achievements in demonstrating femtosecond time-resolved measurements in the water, attosecond pho-toelectron spectroscopy on a liquid microjet and measuring and controlling attosecond charge migration in isolated molecules. We will first concentrate on liquid water to study its electronic dynamics following outer-valence ionization, the formation pathway of the solvated electron and the time scales and intermolecular Coulombic decay following inner-valence or core-level ionization. Second, we will turn to solvated species and measure electronic dynamics and charge migration in solvated molecules, transition-metal complexes and pho-toexcited nanoparticles. These goals will be achieved by developing several innovative experimental tech-niques. We will develop a source of isolated attosecond pulses covering the water window (285-538 eV) and combine it with a flat liquid microjet to realize attosecond transient absorption in liquids. We will complement these measurements with attosecond X-ray emission spectroscopy, Auger spectroscopy and a novel hetero-dyne-detected variant of resonant inelastic Raman scattering, exploiting the large bandwidth that is naturally available from attosecond X-ray sources.
Summary
Charge and energy transfer are the key steps underlying most chemical reactions and biological transformations. The purely electronic dynamics that control such processes take place on attosecond time scales. A complete understanding of these dynamics on the electronic level therefore calls for new experimental methods with attosecond resolution that are applicable to aqueous environments. We propose to combine the element sensitivity of X-ray spectroscopy with attosecond temporal resolution and ultrathin liquid microjets to study electronic dynamics of relevance to chemical, biological and photovoltaic processes. We will build on our recent achievements in demonstrating femtosecond time-resolved measurements in the water, attosecond pho-toelectron spectroscopy on a liquid microjet and measuring and controlling attosecond charge migration in isolated molecules. We will first concentrate on liquid water to study its electronic dynamics following outer-valence ionization, the formation pathway of the solvated electron and the time scales and intermolecular Coulombic decay following inner-valence or core-level ionization. Second, we will turn to solvated species and measure electronic dynamics and charge migration in solvated molecules, transition-metal complexes and pho-toexcited nanoparticles. These goals will be achieved by developing several innovative experimental tech-niques. We will develop a source of isolated attosecond pulses covering the water window (285-538 eV) and combine it with a flat liquid microjet to realize attosecond transient absorption in liquids. We will complement these measurements with attosecond X-ray emission spectroscopy, Auger spectroscopy and a novel hetero-dyne-detected variant of resonant inelastic Raman scattering, exploiting the large bandwidth that is naturally available from attosecond X-ray sources.
Max ERC Funding
2 750 000 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym BactRNA
Project Bacterial small RNAs networks unravelling novel features of transcription and translation
Researcher (PI) Maude Audrey Guillier
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Consolidator Grant (CoG), LS2, ERC-2018-COG
Summary Regulation of gene expression plays a key role in the ability of bacteria to rapidly adapt to changing environments and to colonize extremely diverse habitats. The relatively recent discovery of a plethora of small regulatory RNAs and the beginning of their characterization has unravelled new aspects of bacterial gene expression. First, the expression of many bacterial genes responds to a complex network of both transcriptional and post-transcriptional regulators. However, the properties of the resulting regulatory circuits on the dynamics of gene expression and in the bacterial adaptive response have been poorly addressed so far. In a first part of this project, we will tackle this question by characterizing the circuits that are formed between two widespread classes of bacterial regulators, the sRNAs and the two-component systems, which act at the post-transcriptional and the transcriptional level, respectively. The study of sRNAs also led to major breakthroughs regarding the basic mechanisms of gene expression. In particular, we recently showed that repressor sRNAs can target activating stem-loop structures located within the coding region of mRNAs that promote translation initiation, in striking contrast with the previously recognized inhibitory role of mRNA structures in translation. The second objective of this project is thus to draw an unprecedented map of non-canonical translation initiation events and their regulation by sRNAs.
Overall, this project will greatly improve our understanding of how bacteria can so rapidly and successfully adapt to many different environments, and in the long term, provide clues towards the development of anti-bacterial strategies.
Summary
Regulation of gene expression plays a key role in the ability of bacteria to rapidly adapt to changing environments and to colonize extremely diverse habitats. The relatively recent discovery of a plethora of small regulatory RNAs and the beginning of their characterization has unravelled new aspects of bacterial gene expression. First, the expression of many bacterial genes responds to a complex network of both transcriptional and post-transcriptional regulators. However, the properties of the resulting regulatory circuits on the dynamics of gene expression and in the bacterial adaptive response have been poorly addressed so far. In a first part of this project, we will tackle this question by characterizing the circuits that are formed between two widespread classes of bacterial regulators, the sRNAs and the two-component systems, which act at the post-transcriptional and the transcriptional level, respectively. The study of sRNAs also led to major breakthroughs regarding the basic mechanisms of gene expression. In particular, we recently showed that repressor sRNAs can target activating stem-loop structures located within the coding region of mRNAs that promote translation initiation, in striking contrast with the previously recognized inhibitory role of mRNA structures in translation. The second objective of this project is thus to draw an unprecedented map of non-canonical translation initiation events and their regulation by sRNAs.
Overall, this project will greatly improve our understanding of how bacteria can so rapidly and successfully adapt to many different environments, and in the long term, provide clues towards the development of anti-bacterial strategies.
Max ERC Funding
1 999 754 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym BioDisOrder
Project Order and Disorder at the Surface of Biological Membranes.
Researcher (PI) Alfonso DE SIMONE
Host Institution (HI) UNIVERSITA DEGLI STUDI DI NAPOLI FEDERICO II
Country Italy
Call Details Consolidator Grant (CoG), PE4, ERC-2018-COG
Summary Heterogeneous biomolecular mechanisms at the surface of cellular membranes are often fundamental to generate function and dysfunction in living systems. These processes are governed by transient and dynamical macromolecular interactions that pose tremendous challenges to current analytical tools, as the majority of these methods perform best in the study of well-defined and poorly dynamical systems. This proposal aims at a radical innovation in the characterisation of complex processes that are dominated by structural order and disorder, including those occurring at the surface of biological membranes such as cellular signalling, the assembly of molecular machinery, or the regulation vesicular trafficking.
I outline a programme to realise a vision where the combination of experiments and theory can delineate a new analytical platform to study complex biochemical mechanisms at a multiscale level, and to elucidate their role in physiological and pathological contexts. To achieve this ambitious goal, my research team will develop tools based on the combination of nuclear magnetic resonance (NMR) spectroscopy and molecular simulations, which will enable probing the structure, dynamics, thermodynamics and kinetics of complex protein-protein and protein-membrane interactions occurring at the surface of cellular membranes. The ability to advance both the experimental and theoretical sides, and their combination, is fundamental to define the next generation of methods to achieve our transformative aims. We will provide evidence of the innovative nature of the proposed multiscale approach by addressing some of the great questions in neuroscience and elucidate the details of how functional and aberrant biological complexity is achieved via the fine tuning between structural order and disorder at the neuronal synapse.
Summary
Heterogeneous biomolecular mechanisms at the surface of cellular membranes are often fundamental to generate function and dysfunction in living systems. These processes are governed by transient and dynamical macromolecular interactions that pose tremendous challenges to current analytical tools, as the majority of these methods perform best in the study of well-defined and poorly dynamical systems. This proposal aims at a radical innovation in the characterisation of complex processes that are dominated by structural order and disorder, including those occurring at the surface of biological membranes such as cellular signalling, the assembly of molecular machinery, or the regulation vesicular trafficking.
I outline a programme to realise a vision where the combination of experiments and theory can delineate a new analytical platform to study complex biochemical mechanisms at a multiscale level, and to elucidate their role in physiological and pathological contexts. To achieve this ambitious goal, my research team will develop tools based on the combination of nuclear magnetic resonance (NMR) spectroscopy and molecular simulations, which will enable probing the structure, dynamics, thermodynamics and kinetics of complex protein-protein and protein-membrane interactions occurring at the surface of cellular membranes. The ability to advance both the experimental and theoretical sides, and their combination, is fundamental to define the next generation of methods to achieve our transformative aims. We will provide evidence of the innovative nature of the proposed multiscale approach by addressing some of the great questions in neuroscience and elucidate the details of how functional and aberrant biological complexity is achieved via the fine tuning between structural order and disorder at the neuronal synapse.
Max ERC Funding
1 999 945 €
Duration
Start date: 2019-06-01, End date: 2024-11-30
Project acronym CARBONICE
Project Carbon – Ice Composite Materials: Water Structure and Dynamics at the Carbon Interface
Researcher (PI) Christoph Guenter SALZMANN
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Country United Kingdom
Call Details Consolidator Grant (CoG), PE4, ERC-2016-COG
Summary Carbon and water in its various states of matter make up a substantial proportion of our Universe. The two materials are highly dissimilar with respect to their chemical and physical properties. Elemental carbon is even often referred to as a hydrophobic, ‘water-hating’ material. Yet, the two materials often coexist and critical processes take place at the interface between these unlike chemical species. This includes the hydration shells of hydrophobic moieties in biomolecules, clathrate hydrate materials where water molecules crystallise around hydrophobic guest species as well as icy comets which are often black due to the presence of carbon at their surfaces.
The aim of the CARBONICE project is to investigate the interface and interplay between water and carbon in detail. Using new and innovative experimental strategies, the water molecule will be placed in a variety of different yet highly relevant carbon environments. This will give us unprecedented insights into how water hydrates hydrophobic species which is highly important in the context of hydrophobic interactions. Investigations into how carbon species influence phase transitions of ice will give new insights into crystallisation phenomena but will also reveal the factors that lead to the formation of either ferro- or antiferroelectric ices. Creating carbon – ice composites in the lab as they exist on comets will enable us to understand the complex weather cycles on comets and may help explaining the unusual surface features recently identified by the Rosetta space probe.
In summary, this truly multidisciplinary project opens up a new spyhole to critically important processes at the water – carbon interface. The results will have an impact on the space, atmospheric and general materials sciences but will also be highly relevant with respect to further optimising the computer models of water as well as understanding the properties of water in nano-confinements and how it drives biological processes.
Summary
Carbon and water in its various states of matter make up a substantial proportion of our Universe. The two materials are highly dissimilar with respect to their chemical and physical properties. Elemental carbon is even often referred to as a hydrophobic, ‘water-hating’ material. Yet, the two materials often coexist and critical processes take place at the interface between these unlike chemical species. This includes the hydration shells of hydrophobic moieties in biomolecules, clathrate hydrate materials where water molecules crystallise around hydrophobic guest species as well as icy comets which are often black due to the presence of carbon at their surfaces.
The aim of the CARBONICE project is to investigate the interface and interplay between water and carbon in detail. Using new and innovative experimental strategies, the water molecule will be placed in a variety of different yet highly relevant carbon environments. This will give us unprecedented insights into how water hydrates hydrophobic species which is highly important in the context of hydrophobic interactions. Investigations into how carbon species influence phase transitions of ice will give new insights into crystallisation phenomena but will also reveal the factors that lead to the formation of either ferro- or antiferroelectric ices. Creating carbon – ice composites in the lab as they exist on comets will enable us to understand the complex weather cycles on comets and may help explaining the unusual surface features recently identified by the Rosetta space probe.
In summary, this truly multidisciplinary project opens up a new spyhole to critically important processes at the water – carbon interface. The results will have an impact on the space, atmospheric and general materials sciences but will also be highly relevant with respect to further optimising the computer models of water as well as understanding the properties of water in nano-confinements and how it drives biological processes.
Max ERC Funding
1 999 806 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym CAtMolChip
Project Cold Atmospheric Molecules on a Chip
Researcher (PI) Stephen Dermot Hogan
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Country United Kingdom
Call Details Consolidator Grant (CoG), PE4, ERC-2015-CoG
Summary Highly excited electronic states of small atmospheric molecules play an important, but as yet little explored, role in the reactivity, and in the evolution of plasmas, including the Aurora Borealis, in the upper atmosphere of the Earth. Processes involving these highly excited states are very challenging to investigate theoretically because of the high density of states close to the ionization limits where they lie. Therefore, experimental input is essential for the identification of the reaction and decay mechanisms, and the quantum states of importance in future studies. However, experimental techniques that can be exploited to provide this input have only become available very recently. These techniques permit gas-phase molecular samples in these highly excited states to be confined in traps for sufficient lengths of time (e.g. 1 ms – 10 ms) for detailed studies to be performed in a controlled laboratory environment. They include resonance-enhanced and non-resonance-enhanced multiphoton excitation of long-lived high angular momentum Rydberg states of small molecules, and chip-based devices for efficiently decelerating, transporting and trapping these samples.
With the support of this Consolidator Grant a new experimental research program will be developed in the Department of Physics and Astronomy at University College London involving laboratory based studies of (1) inelastic scattering processes, and (2) the decay mechanisms of gas-phase atmospheric molecules, including N2, O2 and NO, and their constituent atoms, in high Rydberg states. The planned experiments will be directed toward understanding the effects of static and time-dependent electric and magnetic fields, and blackbody radiation fields on slow dissociation processes that occur in highly excited states of N2, O2 and NO, investigations of collisional energy transfer processes, and studies of the role that these excited electronic states play in the evolution and reactivity of atmospheric plasmas incl
Summary
Highly excited electronic states of small atmospheric molecules play an important, but as yet little explored, role in the reactivity, and in the evolution of plasmas, including the Aurora Borealis, in the upper atmosphere of the Earth. Processes involving these highly excited states are very challenging to investigate theoretically because of the high density of states close to the ionization limits where they lie. Therefore, experimental input is essential for the identification of the reaction and decay mechanisms, and the quantum states of importance in future studies. However, experimental techniques that can be exploited to provide this input have only become available very recently. These techniques permit gas-phase molecular samples in these highly excited states to be confined in traps for sufficient lengths of time (e.g. 1 ms – 10 ms) for detailed studies to be performed in a controlled laboratory environment. They include resonance-enhanced and non-resonance-enhanced multiphoton excitation of long-lived high angular momentum Rydberg states of small molecules, and chip-based devices for efficiently decelerating, transporting and trapping these samples.
With the support of this Consolidator Grant a new experimental research program will be developed in the Department of Physics and Astronomy at University College London involving laboratory based studies of (1) inelastic scattering processes, and (2) the decay mechanisms of gas-phase atmospheric molecules, including N2, O2 and NO, and their constituent atoms, in high Rydberg states. The planned experiments will be directed toward understanding the effects of static and time-dependent electric and magnetic fields, and blackbody radiation fields on slow dissociation processes that occur in highly excited states of N2, O2 and NO, investigations of collisional energy transfer processes, and studies of the role that these excited electronic states play in the evolution and reactivity of atmospheric plasmas incl
Max ERC Funding
1 985 553 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym CHAMELEON
Project Cellular Hypoxia Alters DNA MEthylation through Loss of Epigenome OxidatioN
Researcher (PI) Diether Lambrechts
Host Institution (HI) VIB VZW
Country Belgium
Call Details Consolidator Grant (CoG), LS2, ERC-2013-CoG
Summary "DNA methylation was originally described in the 1970s as an epigenetic mark involved in transcriptional silencing, but the existence of DNA demethylation and the enzymes involved in this process were only recently discovered. In particular, it was established that TET hydroxylases catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) through a reaction requiring oxygen (O2) and 2-oxoglutarate (2OG). DNA demethylation as mediated by TET hydroxylases has so far predominantly been studied in the context of stem cells, but its precise contribution to carcinogenesis remains largely enigmatic. Nevertheless, somatic mutations in TETs have been identified in numerous cancers.
Tumor hypoxia is linked to increased malignancy, poor prognosis and resistance to cancer therapies. In this proposal, we aim to assess how hypoxia directly impacts on the cancer epigenome through the dependence of TET-mediated DNA demethylation on O2. First of all, we will study the effect of O2 and 2OG concentration on TET hydroxylase activity, as well as the overall and locus-specific changes of their product (5hmC). Secondly, because much of the hypoxic response is executed through HIFs, we will investigate how HIF binding is influenced by DNA methylation and if so, whether TET hydroxylases are targeted to HIF (or other) binding sites to maintain them transcriptionally active. Thirdly, we will assess to what extent 5hmC profiles differ between tumor types and construct a comprehensive panel of (tumor-specific) 5hmC sites to assess the global and locus-specific relevance of 5hmC in various cancers. Finally, since hypoxia is a key regulator of the cancer stem cell (CSC) niche and within the tumor microenvironment also promotes metastasis, we will establish the in vivo relevance of DNA demethylation, as imposed by tumor hypoxia, in the CSC niche and during metastasis. Overall, we thus aim to establish the interplay between tumor hypoxia and the DNA methylome."
Summary
"DNA methylation was originally described in the 1970s as an epigenetic mark involved in transcriptional silencing, but the existence of DNA demethylation and the enzymes involved in this process were only recently discovered. In particular, it was established that TET hydroxylases catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) through a reaction requiring oxygen (O2) and 2-oxoglutarate (2OG). DNA demethylation as mediated by TET hydroxylases has so far predominantly been studied in the context of stem cells, but its precise contribution to carcinogenesis remains largely enigmatic. Nevertheless, somatic mutations in TETs have been identified in numerous cancers.
Tumor hypoxia is linked to increased malignancy, poor prognosis and resistance to cancer therapies. In this proposal, we aim to assess how hypoxia directly impacts on the cancer epigenome through the dependence of TET-mediated DNA demethylation on O2. First of all, we will study the effect of O2 and 2OG concentration on TET hydroxylase activity, as well as the overall and locus-specific changes of their product (5hmC). Secondly, because much of the hypoxic response is executed through HIFs, we will investigate how HIF binding is influenced by DNA methylation and if so, whether TET hydroxylases are targeted to HIF (or other) binding sites to maintain them transcriptionally active. Thirdly, we will assess to what extent 5hmC profiles differ between tumor types and construct a comprehensive panel of (tumor-specific) 5hmC sites to assess the global and locus-specific relevance of 5hmC in various cancers. Finally, since hypoxia is a key regulator of the cancer stem cell (CSC) niche and within the tumor microenvironment also promotes metastasis, we will establish the in vivo relevance of DNA demethylation, as imposed by tumor hypoxia, in the CSC niche and during metastasis. Overall, we thus aim to establish the interplay between tumor hypoxia and the DNA methylome."
Max ERC Funding
1 920 000 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
Project acronym CHROMATINREPAIRCODE
Project CHROMATIN-REPAIR-CODE: Hacking the chromatin code for DNA repair
Researcher (PI) Haico Van Attikum
Host Institution (HI) ACADEMISCH ZIEKENHUIS LEIDEN
Country Netherlands
Call Details Consolidator Grant (CoG), LS2, ERC-2013-CoG
Summary "Our cells receive tens of thousands of different DNA lesions per day. Failure to repair these lesions will lead to cell death, mutations and genome instability, which contribute to human diseases such as neurodegenerative disorders and cancer. Efficient recognition and repair of DNA damage, however, is complicated by the fact that genomic DNA is packaged, through histone and non-histone proteins, into a condensed structure called chromatin. The DNA repair machinery has to circumvent this barrier to gain access to the damaged DNA and repair the lesions. Our recent work suggests that chromatin-modifying enzymes (CME) help to overcome this barrier at sites of DNA damage. However, the identity of these CME, their mode of action and interconnections with DNA repair pathways remain largely enigmatic. The aim of this project is to systematically identify and characterize the CME that operate during DNA repair processes in both yeast and human cells. To reach this goal we will use a cross-disciplinary approach that combines novel and cutting-edge genomics approaches with bioinformatics, genetics, biochemistry and high-resolution microscopy. Epigenetics-IDentifier (Epi-ID) will be used as a tool to unveil novel CME, whereas RNAi-interference and genetic interaction mapping studies will pinpoint the CME that may potentially regulate repair of DNA damage. A series of functional assays will eventually characterize their role in distinct DNA repair pathways, focusing on those that counteract DNA strand breaks and replication stress. Together these studies will provide insight into how CME assist cells to repair DNA damage in chromatin and inform on the relevance of CME to maintain genome stability and counteract human diseases."
Summary
"Our cells receive tens of thousands of different DNA lesions per day. Failure to repair these lesions will lead to cell death, mutations and genome instability, which contribute to human diseases such as neurodegenerative disorders and cancer. Efficient recognition and repair of DNA damage, however, is complicated by the fact that genomic DNA is packaged, through histone and non-histone proteins, into a condensed structure called chromatin. The DNA repair machinery has to circumvent this barrier to gain access to the damaged DNA and repair the lesions. Our recent work suggests that chromatin-modifying enzymes (CME) help to overcome this barrier at sites of DNA damage. However, the identity of these CME, their mode of action and interconnections with DNA repair pathways remain largely enigmatic. The aim of this project is to systematically identify and characterize the CME that operate during DNA repair processes in both yeast and human cells. To reach this goal we will use a cross-disciplinary approach that combines novel and cutting-edge genomics approaches with bioinformatics, genetics, biochemistry and high-resolution microscopy. Epigenetics-IDentifier (Epi-ID) will be used as a tool to unveil novel CME, whereas RNAi-interference and genetic interaction mapping studies will pinpoint the CME that may potentially regulate repair of DNA damage. A series of functional assays will eventually characterize their role in distinct DNA repair pathways, focusing on those that counteract DNA strand breaks and replication stress. Together these studies will provide insight into how CME assist cells to repair DNA damage in chromatin and inform on the relevance of CME to maintain genome stability and counteract human diseases."
Max ERC Funding
1 999 575 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym chromo-SUMMIT
Project Decoding dynamic chromatin signaling by single-molecule multiplex detection
Researcher (PI) Beat FIERZ
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Consolidator Grant (CoG), PE4, ERC-2016-COG
Summary Transient multivalent interactions are critical for biological processes such as signaling pathways controlling chromatin function. Chromatin, the nucleoprotein complex organizing the genome, is dynamically regulated by post-translational modifications (PTMs) of the chromatin fiber. Protein effectors interact with combinations of these PTMs through multivalent interactions, deposit novel PTMs, thereby propagate signaling cascades and remodel chromatin structure. To reveal the underlying molecular mechanisms, methods outside classical biochemistry are required, in particular due to the combinational complexity of chromatin PTMs and the transient supramolecular interactions crucial for their recognition. Here, we develop a novel approach, where we synthesize arrays of chemically defined designer chromatin fibers and use dynamic multiplex single-molecule imaging to dissect multivalent signaling processes in chromatin. Our studies target a key pathway, the DNA damage response (DDR), which regulates DNA repair processes central to cell survival and is critically implicated in cancer. Detailed knowledge is of utmost importance to develop targeted therapeutic interventions. We thus employ advanced peptide and protein chemistry to generate libraries of chromatin fibers of a defined PTM state that is encoded in the chromatin DNA. With the library immobilized in a flow cell, we use single-molecule detection to directly observe signaling processes by key DDR effectors in real time. Subsequent in situ polony decoding allows the identification of each chromatin fiber’s modification state, enabling broad sampling of signaling outcomes. Finally, we use dynamic computational models to integrate the effector-chromatin interaction network and test key mechanisms in cancer-based cell culture. Together, these methods will yield fundamental insight into chromatin and DDR signaling and will be of broad use for chemical and biomedical research with applications beyond the chromatin field.
Summary
Transient multivalent interactions are critical for biological processes such as signaling pathways controlling chromatin function. Chromatin, the nucleoprotein complex organizing the genome, is dynamically regulated by post-translational modifications (PTMs) of the chromatin fiber. Protein effectors interact with combinations of these PTMs through multivalent interactions, deposit novel PTMs, thereby propagate signaling cascades and remodel chromatin structure. To reveal the underlying molecular mechanisms, methods outside classical biochemistry are required, in particular due to the combinational complexity of chromatin PTMs and the transient supramolecular interactions crucial for their recognition. Here, we develop a novel approach, where we synthesize arrays of chemically defined designer chromatin fibers and use dynamic multiplex single-molecule imaging to dissect multivalent signaling processes in chromatin. Our studies target a key pathway, the DNA damage response (DDR), which regulates DNA repair processes central to cell survival and is critically implicated in cancer. Detailed knowledge is of utmost importance to develop targeted therapeutic interventions. We thus employ advanced peptide and protein chemistry to generate libraries of chromatin fibers of a defined PTM state that is encoded in the chromatin DNA. With the library immobilized in a flow cell, we use single-molecule detection to directly observe signaling processes by key DDR effectors in real time. Subsequent in situ polony decoding allows the identification of each chromatin fiber’s modification state, enabling broad sampling of signaling outcomes. Finally, we use dynamic computational models to integrate the effector-chromatin interaction network and test key mechanisms in cancer-based cell culture. Together, these methods will yield fundamental insight into chromatin and DDR signaling and will be of broad use for chemical and biomedical research with applications beyond the chromatin field.
Max ERC Funding
1 999 815 €
Duration
Start date: 2017-05-01, End date: 2022-10-31