Project acronym AAMDDR
Project DNA damage response and genome stability: The role of ATM, ATR and the Mre11 complex
Researcher (PI) Vincenzo Costanzo
Host Institution (HI) CANCER RESEARCH UK LBG
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.
Summary
Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.
Max ERC Funding
1 000 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym AAS
Project Approximate algebraic structure and applications
Researcher (PI) Ben Green
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Starting Grant (StG), PE1, ERC-2011-StG_20101014
Summary This project studies several mathematical topics with a related theme, all of them part of the relatively new discipline known as additive combinatorics.
We look at approximate, or rough, variants of familiar mathematical notions such as group, polynomial or homomorphism. In each case we seek to describe the structure of these approximate objects, and then to give applications of the resulting theorems. This endeavour has already lead to groundbreaking results in the theory of prime numbers, group theory and combinatorial number theory.
Summary
This project studies several mathematical topics with a related theme, all of them part of the relatively new discipline known as additive combinatorics.
We look at approximate, or rough, variants of familiar mathematical notions such as group, polynomial or homomorphism. In each case we seek to describe the structure of these approximate objects, and then to give applications of the resulting theorems. This endeavour has already lead to groundbreaking results in the theory of prime numbers, group theory and combinatorial number theory.
Max ERC Funding
1 000 000 €
Duration
Start date: 2011-10-01, End date: 2016-09-30
Project acronym AF and MSOGR
Project Automorphic Forms and Moduli Spaces of Galois Representations
Researcher (PI) Toby Gee
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Starting Grant (StG), PE1, ERC-2012-StG_20111012
Summary I propose to establish a research group to develop completely new tools in order to solve three important problems on the relationships between automorphic forms and Galois representations, which lie at the heart of the Langlands program. The first is to prove Serre’s conjecture for real quadratic fields. I will use automorphic induction to transfer the problem to U(4) over the rational numbers, where I will use automorphy lifting theorems and results on the weight part of Serre's conjecture that I established in my earlier work to reduce the problem to proving results in small weight and level. I will prove these base cases via integral p-adic Hodge theory and discriminant bounds.
The second is to develop a geometric theory of moduli spaces of mod p and p-adic Galois representations, and to use it to establish the Breuil–Mézard conjecture in arbitrary dimension, by reinterpreting the conjecture in geometric terms. This will transform the subject by building the first connections between the p-adic Langlands program and the geometric Langlands program, providing an entirely new world of techniques for number theorists. As a consequence of the Breuil-Mézard conjecture, I will be able to deduce far stronger automorphy lifting theorems (in arbitrary dimension) than those currently available.
The third is to completely determine the reduction mod p of certain two-dimensional crystalline representations, and as an application prove a strengthened version of the Gouvêa–Mazur conjecture. I will do this by means of explicit computations with the p-adic local Langlands correspondence for GL_2(Q_p), as well as by improving existing arguments which prove multiplicity one theorems via automorphy lifting theorems. This work will show that the existence of counterexamples to the Gouvêa-Mazur conjecture is due to a purely local phenomenon, and that when this local obstruction vanishes, far stronger conjectures of Buzzard on the slopes of the U_p operator hold.
Summary
I propose to establish a research group to develop completely new tools in order to solve three important problems on the relationships between automorphic forms and Galois representations, which lie at the heart of the Langlands program. The first is to prove Serre’s conjecture for real quadratic fields. I will use automorphic induction to transfer the problem to U(4) over the rational numbers, where I will use automorphy lifting theorems and results on the weight part of Serre's conjecture that I established in my earlier work to reduce the problem to proving results in small weight and level. I will prove these base cases via integral p-adic Hodge theory and discriminant bounds.
The second is to develop a geometric theory of moduli spaces of mod p and p-adic Galois representations, and to use it to establish the Breuil–Mézard conjecture in arbitrary dimension, by reinterpreting the conjecture in geometric terms. This will transform the subject by building the first connections between the p-adic Langlands program and the geometric Langlands program, providing an entirely new world of techniques for number theorists. As a consequence of the Breuil-Mézard conjecture, I will be able to deduce far stronger automorphy lifting theorems (in arbitrary dimension) than those currently available.
The third is to completely determine the reduction mod p of certain two-dimensional crystalline representations, and as an application prove a strengthened version of the Gouvêa–Mazur conjecture. I will do this by means of explicit computations with the p-adic local Langlands correspondence for GL_2(Q_p), as well as by improving existing arguments which prove multiplicity one theorems via automorphy lifting theorems. This work will show that the existence of counterexamples to the Gouvêa-Mazur conjecture is due to a purely local phenomenon, and that when this local obstruction vanishes, far stronger conjectures of Buzzard on the slopes of the U_p operator hold.
Max ERC Funding
1 131 339 €
Duration
Start date: 2012-10-01, End date: 2017-09-30
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
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 APGRAPH
Project Asymptotic Graph Properties
Researcher (PI) Deryk Osthus
Host Institution (HI) THE UNIVERSITY OF BIRMINGHAM
Call Details Starting Grant (StG), PE1, ERC-2012-StG_20111012
Summary Many parts of Graph Theory have witnessed a huge growth over the last years, partly because of their relation to Theoretical Computer Science and Statistical Physics. These connections arise because graphs can be used to model many diverse structures.
The focus of this proposal is on asymptotic results, i.e. the graphs under consideration are large. This often unveils patterns and connections which remain obscure when considering only small graphs.
It also allows for the use of powerful techniques such as probabilistic arguments, which have led to spectacular new developments. In particular, my aim is to make decisive progress on central problems in the following 4 areas:
(1) Factorizations: Factorizations of graphs can be viewed as partitions of the edges of a graph into simple regular structures. They have a rich history and arise in many different settings, such as edge-colouring problems, decomposition problems and in information theory. They also have applications to finding good tours for the famous Travelling salesman problem.
(2) Hamilton cycles: A Hamilton cycle is a cycle which contains all the vertices of the graph. One of the most fundamental problems in Graph Theory/Theoretical Computer Science is to find conditions which guarantee the existence of a Hamilton cycle in a graph.
(3) Embeddings of graphs: This is a natural (but difficult) continuation of the previous question where the aim is to embed more general structures than Hamilton cycles - there has been exciting progress here in recent years which has opened up new avenues.
(4) Resilience of graphs: In many cases, it is important to know whether a graph `strongly’ possesses some property, i.e. one cannot destroy the property by changing a few edges. The systematic study of this notion is a new and rapidly growing area.
I have developed new methods for deep and long-standing problems in these areas which will certainly lead to further applications elsewhere.
Summary
Many parts of Graph Theory have witnessed a huge growth over the last years, partly because of their relation to Theoretical Computer Science and Statistical Physics. These connections arise because graphs can be used to model many diverse structures.
The focus of this proposal is on asymptotic results, i.e. the graphs under consideration are large. This often unveils patterns and connections which remain obscure when considering only small graphs.
It also allows for the use of powerful techniques such as probabilistic arguments, which have led to spectacular new developments. In particular, my aim is to make decisive progress on central problems in the following 4 areas:
(1) Factorizations: Factorizations of graphs can be viewed as partitions of the edges of a graph into simple regular structures. They have a rich history and arise in many different settings, such as edge-colouring problems, decomposition problems and in information theory. They also have applications to finding good tours for the famous Travelling salesman problem.
(2) Hamilton cycles: A Hamilton cycle is a cycle which contains all the vertices of the graph. One of the most fundamental problems in Graph Theory/Theoretical Computer Science is to find conditions which guarantee the existence of a Hamilton cycle in a graph.
(3) Embeddings of graphs: This is a natural (but difficult) continuation of the previous question where the aim is to embed more general structures than Hamilton cycles - there has been exciting progress here in recent years which has opened up new avenues.
(4) Resilience of graphs: In many cases, it is important to know whether a graph `strongly’ possesses some property, i.e. one cannot destroy the property by changing a few edges. The systematic study of this notion is a new and rapidly growing area.
I have developed new methods for deep and long-standing problems in these areas which will certainly lead to further applications elsewhere.
Max ERC Funding
818 414 €
Duration
Start date: 2012-12-01, End date: 2018-11-30
Project acronym ATMINDDR
Project ATMINistrating ATM signalling: exploring the significance of ATM regulation by ATMIN
Researcher (PI) Axel Behrens
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary ATM is the protein kinase that is mutated in the hereditary autosomal recessive disease ataxia telangiectasia (A-T). A-T patients display immune deficiencies, cancer predisposition and radiosensitivity. The molecular role of ATM is to respond to DNA damage by phosphorylating its substrates, thereby promoting repair of damage or arresting the cell cycle. Following the induction of double-strand breaks (DSBs), the NBS1 protein is required for activation of ATM. But ATM can also be activated in the absence of DNA damage. Treatment of cultured cells with hypotonic stress leads to the activation of ATM, presumably due to changes in chromatin structure. We have recently described a second ATM cofactor, ATMIN (ATM INteractor). ATMIN is dispensable for DSBs-induced ATM signalling, but ATM activation following hypotonic stress is mediated by ATMIN. While the biological role of ATM activation by DSBs and NBS1 is well established, the significance, if any, of ATM activation by ATMIN and changes in chromatin was up to now completely enigmatic.
ATM is required for class switch recombination (CSR) and the suppression of translocations in B cells. In order to determine whether ATMIN is required for any of the physiological functions of ATM, we generated a conditional knock-out mouse model for ATMIN. ATM signaling was dramatically reduced following osmotic stress in ATMIN-mutant B cells. ATMIN deficiency led to impaired CSR, and consequently ATMIN-mutant mice developed B cell lymphomas. Thus ablation of ATMIN resulted in a severe defect in ATM function. Our data strongly argue for the existence of a second NBS1-independent mode of ATM activation that is physiologically relevant. While a large amount of scientific effort has gone into characterising ATM signaling triggered by DSBs, essentially nothing is known about NBS1-independent ATM signaling. The experiments outlined in this proposal have the aim to identify and understand the molecular pathway of ATMIN-dependent ATM signaling.
Summary
ATM is the protein kinase that is mutated in the hereditary autosomal recessive disease ataxia telangiectasia (A-T). A-T patients display immune deficiencies, cancer predisposition and radiosensitivity. The molecular role of ATM is to respond to DNA damage by phosphorylating its substrates, thereby promoting repair of damage or arresting the cell cycle. Following the induction of double-strand breaks (DSBs), the NBS1 protein is required for activation of ATM. But ATM can also be activated in the absence of DNA damage. Treatment of cultured cells with hypotonic stress leads to the activation of ATM, presumably due to changes in chromatin structure. We have recently described a second ATM cofactor, ATMIN (ATM INteractor). ATMIN is dispensable for DSBs-induced ATM signalling, but ATM activation following hypotonic stress is mediated by ATMIN. While the biological role of ATM activation by DSBs and NBS1 is well established, the significance, if any, of ATM activation by ATMIN and changes in chromatin was up to now completely enigmatic.
ATM is required for class switch recombination (CSR) and the suppression of translocations in B cells. In order to determine whether ATMIN is required for any of the physiological functions of ATM, we generated a conditional knock-out mouse model for ATMIN. ATM signaling was dramatically reduced following osmotic stress in ATMIN-mutant B cells. ATMIN deficiency led to impaired CSR, and consequently ATMIN-mutant mice developed B cell lymphomas. Thus ablation of ATMIN resulted in a severe defect in ATM function. Our data strongly argue for the existence of a second NBS1-independent mode of ATM activation that is physiologically relevant. While a large amount of scientific effort has gone into characterising ATM signaling triggered by DSBs, essentially nothing is known about NBS1-independent ATM signaling. The experiments outlined in this proposal have the aim to identify and understand the molecular pathway of ATMIN-dependent ATM signaling.
Max ERC Funding
1 499 881 €
Duration
Start date: 2012-02-01, End date: 2018-01-31
Project acronym BEHAVIORAL THEORY
Project Behavioral Theory and Economic Applications
Researcher (PI) Botond Koszegi
Host Institution (HI) KOZEP-EUROPAI EGYETEM
Call Details Starting Grant (StG), SH1, ERC-2012-StG_20111124
Summary "This proposal outlines projects to develop robust and portable theories studying the impact of psychological phenomena in economic settings. The proposed work falls in three broad research agendas.
My first main agenda is to formally model and economically apply a simple observation: that when people make decisions, they do not focus equally on all attributes of their available options, and overweight the attributes they focus on. I will build a set of portable models of focusing in attribute-based choice and risky choice based on the idea that a person focuses more on attributes in which her options differ more. I will also use the framework to develop novel, focus-based, theories of intertemporal choice and social preferences, as well as analyze the implications of focusing for product design, principal-agent relationships, and other economic questions.
My second main agenda is to explore some implications for market outcomes, welfare, and policy of the possibility that consumers misperceive certain aspects of products. I will investigate the circumstances that facilitate the profitable deception of consumers; firms' incentives for ""innovating"" deceptive products, including novel financial products aimed at exploiting investors; how firms' ability to distinguish naive and sophisticated consumers affects the consequences of deception; whether learning on the part of consumers will help them to avoid making mistakes; and how regulators and other observers can detect consumer mistakes from market data.
Two further projects apply the model of reference-dependent utility I have developed in earlier work to understand the pricing and advertising behavior of firms. I will also aim to disseminate some of my work, along with other cutting-edge research in psychology and economics, in a Journal of Economic Literature survey on ""Behavioral Contract Theory."""
Summary
"This proposal outlines projects to develop robust and portable theories studying the impact of psychological phenomena in economic settings. The proposed work falls in three broad research agendas.
My first main agenda is to formally model and economically apply a simple observation: that when people make decisions, they do not focus equally on all attributes of their available options, and overweight the attributes they focus on. I will build a set of portable models of focusing in attribute-based choice and risky choice based on the idea that a person focuses more on attributes in which her options differ more. I will also use the framework to develop novel, focus-based, theories of intertemporal choice and social preferences, as well as analyze the implications of focusing for product design, principal-agent relationships, and other economic questions.
My second main agenda is to explore some implications for market outcomes, welfare, and policy of the possibility that consumers misperceive certain aspects of products. I will investigate the circumstances that facilitate the profitable deception of consumers; firms' incentives for ""innovating"" deceptive products, including novel financial products aimed at exploiting investors; how firms' ability to distinguish naive and sophisticated consumers affects the consequences of deception; whether learning on the part of consumers will help them to avoid making mistakes; and how regulators and other observers can detect consumer mistakes from market data.
Two further projects apply the model of reference-dependent utility I have developed in earlier work to understand the pricing and advertising behavior of firms. I will also aim to disseminate some of my work, along with other cutting-edge research in psychology and economics, in a Journal of Economic Literature survey on ""Behavioral Contract Theory."""
Max ERC Funding
1 275 448 €
Duration
Start date: 2012-11-01, End date: 2018-10-31
Project acronym BIGlobal
Project Firm Growth and Market Power in the Global Economy
Researcher (PI) Swati DHINGRA
Host Institution (HI) LONDON SCHOOL OF ECONOMICS AND POLITICAL SCIENCE
Call Details Starting Grant (StG), SH1, ERC-2017-STG
Summary According to the European Commission, to design effective policies for ensuring a “more dynamic, innovative and competitive” economy, it is essential to understand the decision-making process of firms as they differ a lot in terms of their capacities and policy responses (EC 2007). The objective of my future research is to provide such an analysis. BIGlobal will examine the sources of firm growth and market power to provide new insights into welfare and policy in a globalized world.
Much of analysis of the global economy is set in the paradigm of markets that allocate resources efficiently and there is little role for policy. But big firms dominate economic activity, especially across borders. How do firms grow and what is the effect of their market power on the welfare impact of globalization? This project will determine how firm decisions matter for the aggregate gains from globalization, the division of these gains across different individuals and their implications for policy design.
Over the next five years, I will incorporate richer firms behaviour in models of international trade to understand how trade and industrial policies impact the growth process, especially in less developed markets. The specific questions I will address include: how can trade and competition policy ensure consumers benefit from globalization when firms engaged in international trade have market power, how do domestic policies to encourage agribusiness firms affect the extent to which small farmers gain from trade, how do industrial policies affect firm growth through input linkages, and what is the impact of banking globalization on the growth of firms in the real sector.
Each project will combine theoretical work with rich data from developing economies to expand the frontier of knowledge on trade and industrial policy, and to provide a basis for informed policymaking.
Summary
According to the European Commission, to design effective policies for ensuring a “more dynamic, innovative and competitive” economy, it is essential to understand the decision-making process of firms as they differ a lot in terms of their capacities and policy responses (EC 2007). The objective of my future research is to provide such an analysis. BIGlobal will examine the sources of firm growth and market power to provide new insights into welfare and policy in a globalized world.
Much of analysis of the global economy is set in the paradigm of markets that allocate resources efficiently and there is little role for policy. But big firms dominate economic activity, especially across borders. How do firms grow and what is the effect of their market power on the welfare impact of globalization? This project will determine how firm decisions matter for the aggregate gains from globalization, the division of these gains across different individuals and their implications for policy design.
Over the next five years, I will incorporate richer firms behaviour in models of international trade to understand how trade and industrial policies impact the growth process, especially in less developed markets. The specific questions I will address include: how can trade and competition policy ensure consumers benefit from globalization when firms engaged in international trade have market power, how do domestic policies to encourage agribusiness firms affect the extent to which small farmers gain from trade, how do industrial policies affect firm growth through input linkages, and what is the impact of banking globalization on the growth of firms in the real sector.
Each project will combine theoretical work with rich data from developing economies to expand the frontier of knowledge on trade and industrial policy, and to provide a basis for informed policymaking.
Max ERC Funding
1 313 103 €
Duration
Start date: 2017-12-01, End date: 2022-11-30
Project acronym BIOSYNCEN
Project Dissection of centromeric chromatin and components: A biosynthetic approach
Researcher (PI) Patrick Heun
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Call Details Starting Grant (StG), LS2, ERC-2012-StG_20111109
Summary The centromere is one of the most important chromosomal elements. It is required for proper chromosome segregation in mitosis and meiosis and readily recognizable as the primary constriction of mitotic chromosomes. Proper centromere function is essential to ensure genome stability; therefore understanding centromere identity is directly relevant to cancer biology and gene therapy. How centromeres are established and maintained is however still an open question in the field. In most organisms this appears to be regulated by an epigenetic mechanism. The key candidate for such an epigenetic mark is CENH3 (CENP-A in mammals, CID in Drosophila), a centromere-specific histone H3 variant that is essential for centromere function and exclusively found in the nucleosomes of centromeric chromatin. Using a biosynthetic approach of force-targeting CENH3 in Drosophila to non-centromeric DNA, we were able to induce centromere function and demonstrate that CENH3 is sufficient to determine centromere identity. Here we propose to move this experimental setup across evolutionary boundaries into human cells to develop improved human artificial chromosomes (HACs). We will make further use of this unique setup to dissect the function of targeted CENH3 both in Drosophila and human cells. Contributing centromeric components and histone modifications of centromeric chromatin will be characterized in detail by mass spectroscopy in Drosophila. Finally we are proposing to develop a technique that allows high-resolution mapping of proteins on repetitive DNA to help further characterizing known and novel centromere components. This will be achieved by combining two independently established techniques: DNA methylation and DNA fiber combing. This ambitious proposal will significantly advance our understanding of how centromeres are determined and help the development of improved HACs for therapeutic applications in the future.
Summary
The centromere is one of the most important chromosomal elements. It is required for proper chromosome segregation in mitosis and meiosis and readily recognizable as the primary constriction of mitotic chromosomes. Proper centromere function is essential to ensure genome stability; therefore understanding centromere identity is directly relevant to cancer biology and gene therapy. How centromeres are established and maintained is however still an open question in the field. In most organisms this appears to be regulated by an epigenetic mechanism. The key candidate for such an epigenetic mark is CENH3 (CENP-A in mammals, CID in Drosophila), a centromere-specific histone H3 variant that is essential for centromere function and exclusively found in the nucleosomes of centromeric chromatin. Using a biosynthetic approach of force-targeting CENH3 in Drosophila to non-centromeric DNA, we were able to induce centromere function and demonstrate that CENH3 is sufficient to determine centromere identity. Here we propose to move this experimental setup across evolutionary boundaries into human cells to develop improved human artificial chromosomes (HACs). We will make further use of this unique setup to dissect the function of targeted CENH3 both in Drosophila and human cells. Contributing centromeric components and histone modifications of centromeric chromatin will be characterized in detail by mass spectroscopy in Drosophila. Finally we are proposing to develop a technique that allows high-resolution mapping of proteins on repetitive DNA to help further characterizing known and novel centromere components. This will be achieved by combining two independently established techniques: DNA methylation and DNA fiber combing. This ambitious proposal will significantly advance our understanding of how centromeres are determined and help the development of improved HACs for therapeutic applications in the future.
Max ERC Funding
1 755 960 €
Duration
Start date: 2013-02-01, End date: 2019-01-31
Project acronym CatDT
Project Categorified Donaldson-Thomas Theory
Researcher (PI) Nicholas David James (Ben) DAVISON
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Call Details Starting Grant (StG), PE1, ERC-2017-STG
Summary According to string theory, coherent sheaves on three-dimensional Calabi-Yau spaces encode fundamental properties of the universe. On the other hand, they have a purely mathematical definition. We will develop and use the new field of categorified Donaldson-Thomas (DT) theory, which counts these objects. Via the powerful perspective of noncommutative algebraic geometry, this theory has found application in recent years in a wide variety of contexts, far from classical algebraic geometry.
Categorification has proved tremendously powerful across mathematics, for example the entire subject of algebraic topology was started by the categorification of Betti numbers. The categorification of DT theory leads to the replacement of the numbers of DT theory by vector spaces, of which these numbers are the dimensions. In the area of categorified DT theory we have been able to prove fundamental conjectures upgrading the famous wall crossing formula and integrality conjecture in noncommutative algebraic geometry. The first three projects involve applications of the resulting new subject:
1. Complete the categorification of quantum cluster algebras, proving the strong positivity conjecture.
2. Use cohomological DT theory to prove the outstanding conjectures in the nonabelian Hodge theory of Riemann surfaces, and the subject of Higgs bundles.
3. Prove the comparison conjecture, realising the study of Yangian quantum groups and the geometric representation theory around them as a special case of DT theory.
The final objective involves coming full circle, and applying our recent advances in noncommutative DT theory to the original theory that united string theory with algebraic geometry:
4. Develop a generalised theory of categorified DT theory extending our results in noncommutative DT theory, proving the integrality conjecture for categories of coherent sheaves on Calabi-Yau 3-folds.
Summary
According to string theory, coherent sheaves on three-dimensional Calabi-Yau spaces encode fundamental properties of the universe. On the other hand, they have a purely mathematical definition. We will develop and use the new field of categorified Donaldson-Thomas (DT) theory, which counts these objects. Via the powerful perspective of noncommutative algebraic geometry, this theory has found application in recent years in a wide variety of contexts, far from classical algebraic geometry.
Categorification has proved tremendously powerful across mathematics, for example the entire subject of algebraic topology was started by the categorification of Betti numbers. The categorification of DT theory leads to the replacement of the numbers of DT theory by vector spaces, of which these numbers are the dimensions. In the area of categorified DT theory we have been able to prove fundamental conjectures upgrading the famous wall crossing formula and integrality conjecture in noncommutative algebraic geometry. The first three projects involve applications of the resulting new subject:
1. Complete the categorification of quantum cluster algebras, proving the strong positivity conjecture.
2. Use cohomological DT theory to prove the outstanding conjectures in the nonabelian Hodge theory of Riemann surfaces, and the subject of Higgs bundles.
3. Prove the comparison conjecture, realising the study of Yangian quantum groups and the geometric representation theory around them as a special case of DT theory.
The final objective involves coming full circle, and applying our recent advances in noncommutative DT theory to the original theory that united string theory with algebraic geometry:
4. Develop a generalised theory of categorified DT theory extending our results in noncommutative DT theory, proving the integrality conjecture for categories of coherent sheaves on Calabi-Yau 3-folds.
Max ERC Funding
1 239 435 €
Duration
Start date: 2017-11-01, End date: 2022-10-31
