Project acronym ALTERUMMA
Project Creating an Alternative umma: Clerical Authority and Religio-political Mobilisation in Transnational Shii Islam
Researcher (PI) Oliver Paul SCHARBRODT
Host Institution (HI) THE UNIVERSITY OF BIRMINGHAM
Country United Kingdom
Call Details Consolidator Grant (CoG), SH5, ERC-2016-COG
Summary This interdisciplinary project investigates the transformation of Shii Islam in the Middle East and Europe since the 1950s. The project examines the formation of modern Shii communal identities and the role Shii clerical authorities and their transnational networks have played in their religio-political mobilisation. The volatile situation post-Arab Spring, the rise of militant movements such as ISIS and the sectarianisation of geopolitical conflicts in the Middle East have intensified efforts to forge distinct Shii communal identities and to conceive Shii Muslims as part of an alternative umma (Islamic community). The project focusses on Iran, Iraq and significant but unexplored diasporic links to Syria, Kuwait and Britain. In response to the rise of modern nation-states in the Middle East, Shii clerical authorities resorted to a wide range of activities: (a) articulating intellectual responses to the ideologies underpinning modern Middle Eastern nation-states, (b) forming political parties and other platforms of socio-political activism and (c) using various forms of cultural production by systematising and promoting Shii ritual practices and utilising visual art, poetry and new media.
The project yields a perspectival shift on the factors that led to Shii communal mobilisation by:
- Analysing unacknowledged intellectual responses of Shii clerical authorities to the secular or sectarian ideologies of post-colonial nation-states and to the current sectarianisation of geopolitics in the Middle East.
- Emphasising the central role of diasporic networks in the Middle East and Europe in mobilising Shii communities and in influencing discourses and agendas of clerical authorities based in Iraq and Iran.
- Exploring new modes of cultural production in the form of a modern Shii aesthetics articulated in ritual practices, visual art, poetry and new media and thus creating a more holistic narrative on Shii religio-political mobilisation.
Summary
This interdisciplinary project investigates the transformation of Shii Islam in the Middle East and Europe since the 1950s. The project examines the formation of modern Shii communal identities and the role Shii clerical authorities and their transnational networks have played in their religio-political mobilisation. The volatile situation post-Arab Spring, the rise of militant movements such as ISIS and the sectarianisation of geopolitical conflicts in the Middle East have intensified efforts to forge distinct Shii communal identities and to conceive Shii Muslims as part of an alternative umma (Islamic community). The project focusses on Iran, Iraq and significant but unexplored diasporic links to Syria, Kuwait and Britain. In response to the rise of modern nation-states in the Middle East, Shii clerical authorities resorted to a wide range of activities: (a) articulating intellectual responses to the ideologies underpinning modern Middle Eastern nation-states, (b) forming political parties and other platforms of socio-political activism and (c) using various forms of cultural production by systematising and promoting Shii ritual practices and utilising visual art, poetry and new media.
The project yields a perspectival shift on the factors that led to Shii communal mobilisation by:
- Analysing unacknowledged intellectual responses of Shii clerical authorities to the secular or sectarian ideologies of post-colonial nation-states and to the current sectarianisation of geopolitics in the Middle East.
- Emphasising the central role of diasporic networks in the Middle East and Europe in mobilising Shii communities and in influencing discourses and agendas of clerical authorities based in Iraq and Iran.
- Exploring new modes of cultural production in the form of a modern Shii aesthetics articulated in ritual practices, visual art, poetry and new media and thus creating a more holistic narrative on Shii religio-political mobilisation.
Max ERC Funding
1 952 374 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym ARCTIC CULT
Project ARCTIC CULTURES: SITES OF COLLECTION IN THE FORMATION OF THE EUROPEAN AND AMERICAN NORTHLANDS
Researcher (PI) Richard Charles POWELL
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Country United Kingdom
Call Details Consolidator Grant (CoG), SH5, ERC-2016-COG
Summary The Arctic has risen to global attention in recent years, as it has been reconfigured through debates about global environmental change, resource extraction and disputes over sovereign rights. Within these discourses, little attention has been paid to the cultures of the Arctic. Indeed, it often seems as if the Circumpolar Arctic in global public understanding remains framed as a 'natural region' - that is, a place where the environment dominates the creation of culture. This framing has consequences for the region, because through this the Arctic becomes constructed as a space where people are absent. This proposal aims to discover how and why this might be so.
The proposal argues that this construction of the Arctic emerged from the exploration of the region by Europeans and North Americans and their contacts with indigenous people from the middle of the eighteenth century. Particular texts, cartographic representations and objects were collected and returned to sites like London, Copenhagen, Berlin and Philadelphia. The construction of the Arctic thereby became entwined within the growth of colonial museum cultures and, indeed, western modernity. This project aims to delineate the networks and collecting cultures involved in this creation of Arctic Cultures. It will bring repositories in colonial metropoles into dialogue with sites of collection in the Arctic by tracing the contexts of discovery and memorialisation. In doing so, it aspires to a new understanding of the consequences of certain forms of colonial representation for debates about the Circumpolar Arctic today.
The project involves research by the Principal Investigator and four Post Doctoral Researchers at museums, archives, libraries and repositories across Europe and North America, as well as in Greenland and the Canadian Arctic. A Project Assistant based in Oxford will help facilitate the completion of the research.
Summary
The Arctic has risen to global attention in recent years, as it has been reconfigured through debates about global environmental change, resource extraction and disputes over sovereign rights. Within these discourses, little attention has been paid to the cultures of the Arctic. Indeed, it often seems as if the Circumpolar Arctic in global public understanding remains framed as a 'natural region' - that is, a place where the environment dominates the creation of culture. This framing has consequences for the region, because through this the Arctic becomes constructed as a space where people are absent. This proposal aims to discover how and why this might be so.
The proposal argues that this construction of the Arctic emerged from the exploration of the region by Europeans and North Americans and their contacts with indigenous people from the middle of the eighteenth century. Particular texts, cartographic representations and objects were collected and returned to sites like London, Copenhagen, Berlin and Philadelphia. The construction of the Arctic thereby became entwined within the growth of colonial museum cultures and, indeed, western modernity. This project aims to delineate the networks and collecting cultures involved in this creation of Arctic Cultures. It will bring repositories in colonial metropoles into dialogue with sites of collection in the Arctic by tracing the contexts of discovery and memorialisation. In doing so, it aspires to a new understanding of the consequences of certain forms of colonial representation for debates about the Circumpolar Arctic today.
The project involves research by the Principal Investigator and four Post Doctoral Researchers at museums, archives, libraries and repositories across Europe and North America, as well as in Greenland and the Canadian Arctic. A Project Assistant based in Oxford will help facilitate the completion of the research.
Max ERC Funding
1 996 250 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym CSRS
Project A Comparative Study of Resilience in Survivors of War Rape and Sexual Violence: New Directions for Transitional Justice
Researcher (PI) Janine Clark
Host Institution (HI) THE UNIVERSITY OF BIRMINGHAM
Country United Kingdom
Call Details Consolidator Grant (CoG), SH2, ERC-2016-COG
Summary The profound trauma associated with rape and sexual violence in conflict has been extensively explored within existing scholarship. The fact that many survivors exhibit remarkable post-trauma resilience, however, remains critically under-investigated. CSRS will address this fundamental gap by undertaking a paradigm-shifting empirical study of the underlying conditions for resilience. It will then use this data to pioneer a new, survivor-centred model of transitional justice – the process of redressing the legacy of massive human rights abuses.
Using the three comparative case studies of Bosnia-Hercegovina (BiH), the Democratic Republic of Congo (DRC) and Colombia, and adopting a social-ecological approach that emphasizes the interactions between individuals and their environments, CSRS consists of two inter-linked parts. The first part will involve extensive fieldwork, using a combination of quantitative and qualitative research methods, to generate a rich cross-cultural dataset that identifies and explains the key micro, meso and macro factors that foster resilience in survivors of war rape and sexual violence.
The second part of CSRS will use this dataset to build an innovative, bottom-up model of transitional justice that prioritizes the long-term needs of survivors, reflecting the project’s hypothesis that a positive correlation exists between fulfilment of needs and resilience. This model will be developed with the input of survivors in BiH, the DRC and Colombia and in consultation with transitional justice scholars and practitioners. CSRS aims to transform transitional justice theory and practice. The project outputs will therefore include both academic publications and policy reports to communicate the model to the governments of the case study countries, the United Nations and a wider international audience with the overall aim of making empowerment and resilience part of a new transitional justice agenda.
Summary
The profound trauma associated with rape and sexual violence in conflict has been extensively explored within existing scholarship. The fact that many survivors exhibit remarkable post-trauma resilience, however, remains critically under-investigated. CSRS will address this fundamental gap by undertaking a paradigm-shifting empirical study of the underlying conditions for resilience. It will then use this data to pioneer a new, survivor-centred model of transitional justice – the process of redressing the legacy of massive human rights abuses.
Using the three comparative case studies of Bosnia-Hercegovina (BiH), the Democratic Republic of Congo (DRC) and Colombia, and adopting a social-ecological approach that emphasizes the interactions between individuals and their environments, CSRS consists of two inter-linked parts. The first part will involve extensive fieldwork, using a combination of quantitative and qualitative research methods, to generate a rich cross-cultural dataset that identifies and explains the key micro, meso and macro factors that foster resilience in survivors of war rape and sexual violence.
The second part of CSRS will use this dataset to build an innovative, bottom-up model of transitional justice that prioritizes the long-term needs of survivors, reflecting the project’s hypothesis that a positive correlation exists between fulfilment of needs and resilience. This model will be developed with the input of survivors in BiH, the DRC and Colombia and in consultation with transitional justice scholars and practitioners. CSRS aims to transform transitional justice theory and practice. The project outputs will therefore include both academic publications and policy reports to communicate the model to the governments of the case study countries, the United Nations and a wider international audience with the overall aim of making empowerment and resilience part of a new transitional justice agenda.
Max ERC Funding
1 790 580 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym FluCoMa
Project Fluid Corpus Manipulation: Creative Research in Musical Mining of Large Sound/Gesture Datasets through Foundational Access to the Latest Advances of Signal Decomposition.
Researcher (PI) Pierre Alexandre Tremblay
Host Institution (HI) UNIVERSITY OF HUDDERSFIELD
Country United Kingdom
Call Details Consolidator Grant (CoG), SH5, ERC-2016-COG
Summary The FluCoMA project instigates new musical ways of exploiting ever-growing banks of sound and gestures within the digital composition process by bringing breakthroughs of signal decomposition DSP to the toolset of techno-fluent computer composers for the first time.
Cutting-edge musical composition has always been dependent on, critical and subversive of the latest advances of technology. Unfortunately, there is a contemporary challenge inherent to aesthetic research in computer composition: an ever-expanding gap between DSP advances and their availability to musical investigators.
One such advance is signal decomposition: a sound can now be separated into its transient, pitched, and residual constituents. These potent algorithms are partially available in closed software, or in laboratories, but not at a suitable level of modularity within the coding environments used by the creative researchers (Max and SuperCollider) to allow groundbreaking sonic research into a rich unexploited area: the manipulation of large sound corpora. Indeed, with access to, genesis of, and storage of large sound banks now commonplace, novel ways of abstracting and manipulating them are needed to mine their inherent potential.
FluCoMa proposes to tackle this issue by bridging this gap, empowering techno-fluent aesthetic researchers with a toolset for signal decomposition within their mastered software environments, in order to experiment with new sound and gesture design untapped in large corpora. The three degrees of manipulations to be explored are (1) expressive browsing and descriptor-based taxonomy, (2) remixing, component replacement, and hybridisation by concatenation, and (3) pattern recognition at component level, with interpolating and variation making potential. These novel manipulations will yield new sounds, new musical ideas, and new approaches to large corpora. At present, no library exists allowing such cutting-edge research on creative fluid corpus manipulations to be done
Summary
The FluCoMA project instigates new musical ways of exploiting ever-growing banks of sound and gestures within the digital composition process by bringing breakthroughs of signal decomposition DSP to the toolset of techno-fluent computer composers for the first time.
Cutting-edge musical composition has always been dependent on, critical and subversive of the latest advances of technology. Unfortunately, there is a contemporary challenge inherent to aesthetic research in computer composition: an ever-expanding gap between DSP advances and their availability to musical investigators.
One such advance is signal decomposition: a sound can now be separated into its transient, pitched, and residual constituents. These potent algorithms are partially available in closed software, or in laboratories, but not at a suitable level of modularity within the coding environments used by the creative researchers (Max and SuperCollider) to allow groundbreaking sonic research into a rich unexploited area: the manipulation of large sound corpora. Indeed, with access to, genesis of, and storage of large sound banks now commonplace, novel ways of abstracting and manipulating them are needed to mine their inherent potential.
FluCoMa proposes to tackle this issue by bridging this gap, empowering techno-fluent aesthetic researchers with a toolset for signal decomposition within their mastered software environments, in order to experiment with new sound and gesture design untapped in large corpora. The three degrees of manipulations to be explored are (1) expressive browsing and descriptor-based taxonomy, (2) remixing, component replacement, and hybridisation by concatenation, and (3) pattern recognition at component level, with interpolating and variation making potential. These novel manipulations will yield new sounds, new musical ideas, and new approaches to large corpora. At present, no library exists allowing such cutting-edge research on creative fluid corpus manipulations to be done
Max ERC Funding
1 997 431 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym GALOP
Project Galois theory of periods and applications.
Researcher (PI) Francis Clement Sais BROWN
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Consolidator Grant (CoG), PE1, ERC-2016-COG
Summary A period is a complex number defined by the integral of an algebraic differential form over a region defined by polynomial inequalities. Examples include: algebraic numbers, elliptic integrals, and Feynman integrals in high-energy physics. Many problems in mathematics can be cast as a statement involving periods. A deep idea, based on Grothendieck's philosophy of motives, is that there should be a Galois theory of periods, generalising classical Galois theory for algebraic numbers. This reposes on inaccessible conjectures in transcendence theory, but these can be circumvented in many important cases using an elementary notion of motivic periods. This allows one to set up a working Galois theory of periods in many situations of arithmetic and physical interest.
These ideas grew out of the PI's recent proof of the Deligne-Ihara conjecture, in which the Galois theory of multiple zeta values was worked out. Multiple zeta values are one of the most fundamental families of periods, and their Galois group plays an important role in mathematics: it is conjecturally equal to Drinfeld's Grothendieck-Teichmuller group, the stable derivation algebra on moduli spaces of curves, and the Galois group of mixed Tate motives over the integers. It occurs in deformation quantization, the homology of the graph complex, and the Kashiwara-Vergne problem, as well as having numerous connections to string theory, and quantum field theory.
The goal of this proposal is to generalise this picture. Periods of moduli spaces of curves, multiple L-functions of modular forms, and Feynman amplitudes in quantum field and string theory should each have their own Galois theory
which is yet to be worked out.
This is completely uncharted territory, and will have numerous applications to number theory, algebraic geometry and physics.
Summary
A period is a complex number defined by the integral of an algebraic differential form over a region defined by polynomial inequalities. Examples include: algebraic numbers, elliptic integrals, and Feynman integrals in high-energy physics. Many problems in mathematics can be cast as a statement involving periods. A deep idea, based on Grothendieck's philosophy of motives, is that there should be a Galois theory of periods, generalising classical Galois theory for algebraic numbers. This reposes on inaccessible conjectures in transcendence theory, but these can be circumvented in many important cases using an elementary notion of motivic periods. This allows one to set up a working Galois theory of periods in many situations of arithmetic and physical interest.
These ideas grew out of the PI's recent proof of the Deligne-Ihara conjecture, in which the Galois theory of multiple zeta values was worked out. Multiple zeta values are one of the most fundamental families of periods, and their Galois group plays an important role in mathematics: it is conjecturally equal to Drinfeld's Grothendieck-Teichmuller group, the stable derivation algebra on moduli spaces of curves, and the Galois group of mixed Tate motives over the integers. It occurs in deformation quantization, the homology of the graph complex, and the Kashiwara-Vergne problem, as well as having numerous connections to string theory, and quantum field theory.
The goal of this proposal is to generalise this picture. Periods of moduli spaces of curves, multiple L-functions of modular forms, and Feynman amplitudes in quantum field and string theory should each have their own Galois theory
which is yet to be worked out.
This is completely uncharted territory, and will have numerous applications to number theory, algebraic geometry and physics.
Max ERC Funding
1 997 959 €
Duration
Start date: 2017-03-01, End date: 2022-08-31
Project acronym MaintainMeth
Project Quantitative analysis of DNA methylation maintenance within chromatin
Researcher (PI) Daniel ZILBERMAN
Host Institution (HI) JOHN INNES CENTRE
Country United Kingdom
Call Details Consolidator Grant (CoG), LS2, ERC-2016-COG
Summary Cytosine methylation is a chemical modification that is precisely copied when DNA is replicated. Because methylation can regulate gene expression, accurate reproduction of DNA methylation patterns is essential for plant and animal development and for human health. The enzymes that maintain DNA methylation have to work within chromatin, and particularly to contend with nucleosomes – tight complexes of DNA and histone proteins. How methylation of nucleosomal DNA is maintained remains unknown, and even the simple matter of whether nucleosomes hinder or promote methylation is controversial.
My laboratory’s recent work with DDM1 – an ancient protein conserved between plants and animals that can move nucleosomes – and linker histone H1, which binds to nucleosomes and the intervening ‘linker’ DNA, has allowed us to formulate a model wherein movement of nucleosomes by DDM1 dislodges H1 and allows methyltransferases to access the DNA. Furthermore, this work revealed the existence of unknown factors required to maintain DNA methylation. My laboratory also discovered that DNA methylation influences nucleosome placement, thereby demonstrating that the interaction between DNA methylation and nucleosomes is bidirectional.
My goal is now to deeply understand the connected processes of maintenance methylation and nucleosome placement. This will be achieved through three interconnected research strands:
1) Elucidation of how DNA methylation is maintained within chromatin.
2) Identification of new DNA methylation maintenance factors.
3) Determination of how DNA methylation influences nucleosomes in vivo.
Our ultimate output will be the creation of a mathematical model of DNA methylation maintenance that will incorporate the bidirectional interactions between methylation and nucleosomes. This breakthrough will revolutionize research in the field by permitting the development of precise, quantitative hypotheses about the maintenance and function of DNA methylation within chromatin.
Summary
Cytosine methylation is a chemical modification that is precisely copied when DNA is replicated. Because methylation can regulate gene expression, accurate reproduction of DNA methylation patterns is essential for plant and animal development and for human health. The enzymes that maintain DNA methylation have to work within chromatin, and particularly to contend with nucleosomes – tight complexes of DNA and histone proteins. How methylation of nucleosomal DNA is maintained remains unknown, and even the simple matter of whether nucleosomes hinder or promote methylation is controversial.
My laboratory’s recent work with DDM1 – an ancient protein conserved between plants and animals that can move nucleosomes – and linker histone H1, which binds to nucleosomes and the intervening ‘linker’ DNA, has allowed us to formulate a model wherein movement of nucleosomes by DDM1 dislodges H1 and allows methyltransferases to access the DNA. Furthermore, this work revealed the existence of unknown factors required to maintain DNA methylation. My laboratory also discovered that DNA methylation influences nucleosome placement, thereby demonstrating that the interaction between DNA methylation and nucleosomes is bidirectional.
My goal is now to deeply understand the connected processes of maintenance methylation and nucleosome placement. This will be achieved through three interconnected research strands:
1) Elucidation of how DNA methylation is maintained within chromatin.
2) Identification of new DNA methylation maintenance factors.
3) Determination of how DNA methylation influences nucleosomes in vivo.
Our ultimate output will be the creation of a mathematical model of DNA methylation maintenance that will incorporate the bidirectional interactions between methylation and nucleosomes. This breakthrough will revolutionize research in the field by permitting the development of precise, quantitative hypotheses about the maintenance and function of DNA methylation within chromatin.
Max ERC Funding
2 749 962 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym PAIXUE
Project Classicising learning in medieval imperial systems: Cross-cultural approaches to Byzantine paideia and Tang/Song xue
Researcher (PI) Niels Henrik GAUL
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Country United Kingdom
Call Details Consolidator Grant (CoG), SH5, ERC-2016-COG
Summary In the medieval Eurasian geopolitical space, Byzantium and China stand out as two centralised imperial orders that drew on seemingly unbroken, in fact purposely constructed, traditions of classicising learning. PAIXUE examines in tandem, with equal focus on structural parallels and divergences, the conscious revival and subsequent dialectics of classicising learning in middle and later Byzantium (c.800–1350) and Tang/Song China (618–1279). Initially tied into aristocratic culture, it became a tool by which the imperial state sought to monopolise prestige and access to power so as to effectively channel the activities of newly emerging burgeoning ‘middling’ strata into the service of empire. As time progressed, it was also the basis upon which these new elites constructed novel forms of subjectivity that claimed authority and agency increasingly independent of the imperial state.
PAIXUE traces this evolution of classicising learning in Byzantine and Tang/Song literati culture from two angles. The rst examines the galvanising function of social performances that involved classicising learning in the imperial systems. The second places the individual literatus centre-stage and explores the transformations of self-awareness, ethos, and self-cultivation. Given PAIXUE’s concern with examining phenomena cross-culturally in the longue-durée, rather than merely juxtaposing ‘spotlight’ impressions, a comparison of these two imperial systems does not only allow for deeper insights into the historical development of both China and Byzantium: it opens the possibility of studying cultural mechanisms behind the formation of institutions, practices and values. The project explores novel forms of collaboration in the humanities, including the co-authoring of research output between Byzantinists and Sinologists. Byzantium, frequently perceived as the ‘Other’ within western culture to the present day, serves here to build meaningful bridges to (pre-modern) China.
Summary
In the medieval Eurasian geopolitical space, Byzantium and China stand out as two centralised imperial orders that drew on seemingly unbroken, in fact purposely constructed, traditions of classicising learning. PAIXUE examines in tandem, with equal focus on structural parallels and divergences, the conscious revival and subsequent dialectics of classicising learning in middle and later Byzantium (c.800–1350) and Tang/Song China (618–1279). Initially tied into aristocratic culture, it became a tool by which the imperial state sought to monopolise prestige and access to power so as to effectively channel the activities of newly emerging burgeoning ‘middling’ strata into the service of empire. As time progressed, it was also the basis upon which these new elites constructed novel forms of subjectivity that claimed authority and agency increasingly independent of the imperial state.
PAIXUE traces this evolution of classicising learning in Byzantine and Tang/Song literati culture from two angles. The rst examines the galvanising function of social performances that involved classicising learning in the imperial systems. The second places the individual literatus centre-stage and explores the transformations of self-awareness, ethos, and self-cultivation. Given PAIXUE’s concern with examining phenomena cross-culturally in the longue-durée, rather than merely juxtaposing ‘spotlight’ impressions, a comparison of these two imperial systems does not only allow for deeper insights into the historical development of both China and Byzantium: it opens the possibility of studying cultural mechanisms behind the formation of institutions, practices and values. The project explores novel forms of collaboration in the humanities, including the co-authoring of research output between Byzantinists and Sinologists. Byzantium, frequently perceived as the ‘Other’ within western culture to the present day, serves here to build meaningful bridges to (pre-modern) China.
Max ERC Funding
1 999 155 €
Duration
Start date: 2017-08-01, End date: 2022-07-31
Project acronym RepTime
Project Molecular control of DNA replication timing in mammalian cells
Researcher (PI) Sara Cristiana Barbara BUONOMO
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Country United Kingdom
Call Details Consolidator Grant (CoG), LS3, ERC-2016-COG
Summary DNA replication is an essential process ensuring the transmission of genetic information and is highly regulated. Specifically, the DNA replication-timing program ensures that the sites of initiation of DNA replication, termed origins, are not all activated simultaneously but follow a cell-type specific schedule. This pathway is conserved throughout eukaryotic evolution, however its molecular control and biological role are not fully understood. In this proposal I aim to understand key aspects of replication-timing program by employing a combination of advanced mouse genetics, genomics, cell biology and proteomics. Currently one of the major limitations in the mammalian DNA replication field is the elusive identity of origins. I aim to comprehensively map origins in a variety of mouse cells/tissues and relate the regulation of origin firing to the control of gene expression and three-dimensional nuclear architecture. I have discovered that Rif1 controls replication timing and links it to nuclear three-dimensional organization. I have also revealed the existence of a novel Rif1-independent pathway that controls the timing of a significant fraction of the late-replicating genome, identified by constitutive association with a key nuclear architecture component, Lamin B1. Here, I propose complementary approaches to understand the molecular mechanism by which Rif1 coordinates replication timing and nuclear organization as well as the molecular underpinnings of the novel pathway instructing late-replication in Lamin B1-associated regions. Finally, my goal is to understand the in vivo biological role of the replication-timing program. Our preliminary data identify mammalian X inactivation as a process where replication timing may play a fundamental part. My ultimate objective is to contribute to the realization of a comprehensive understanding of nuclear function, integrating the co-regulation of DNA replication with gene expression, epigenetic inheritance and DNA repair.
Summary
DNA replication is an essential process ensuring the transmission of genetic information and is highly regulated. Specifically, the DNA replication-timing program ensures that the sites of initiation of DNA replication, termed origins, are not all activated simultaneously but follow a cell-type specific schedule. This pathway is conserved throughout eukaryotic evolution, however its molecular control and biological role are not fully understood. In this proposal I aim to understand key aspects of replication-timing program by employing a combination of advanced mouse genetics, genomics, cell biology and proteomics. Currently one of the major limitations in the mammalian DNA replication field is the elusive identity of origins. I aim to comprehensively map origins in a variety of mouse cells/tissues and relate the regulation of origin firing to the control of gene expression and three-dimensional nuclear architecture. I have discovered that Rif1 controls replication timing and links it to nuclear three-dimensional organization. I have also revealed the existence of a novel Rif1-independent pathway that controls the timing of a significant fraction of the late-replicating genome, identified by constitutive association with a key nuclear architecture component, Lamin B1. Here, I propose complementary approaches to understand the molecular mechanism by which Rif1 coordinates replication timing and nuclear organization as well as the molecular underpinnings of the novel pathway instructing late-replication in Lamin B1-associated regions. Finally, my goal is to understand the in vivo biological role of the replication-timing program. Our preliminary data identify mammalian X inactivation as a process where replication timing may play a fundamental part. My ultimate objective is to contribute to the realization of a comprehensive understanding of nuclear function, integrating the co-regulation of DNA replication with gene expression, epigenetic inheritance and DNA repair.
Max ERC Funding
1 999 785 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym Survive
Project Surviving metabolism: acid handling and signalling
Researcher (PI) Pawel Dominik SWIETACH
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Consolidator Grant (CoG), LS4, ERC-2016-COG
Summary Metabolism generates vast quantities of acid, which exerts broad-spectrum biological effects because protein protonation is a powerful post-translational modification. Regulation of intracellular pH (pHi) is therefore a homeostatic priority, but carefully orchestrated proton dynamics are a versatile signal.
Extracellular acidity is an established chemical signature of tumours and has recently been proposed to convey a signal that shapes the phenotypic landscape of cancer. Cancer’s genetic instability yields diversity in acid handling and signalling, forming a substrate for selection under acid-stress. This is a plausible mechanism for disease progression and an analogy can be drawn to experimentally-verified hypoxic selection.
Current models of acid handling in cancer are, however, based on population-averages of observations made at the cell level. This fails to appreciate diversity and the complexity inherent in tissues. We will produce a more complete understanding of acid handling that accounts for diffusive transport across tissue compartments and the role of the tumour stroma. A systems-approach of characterising pH-regulatory processes cell-by-cell will identify which components are liable to vary, and thus are a substrate for acid-driven somatic evolution.
The long-term effects of proton signals on gene expression have not been tested, despite evidence for proton-sensing transcription factors. To address the mechanism for adaptation to acid-stress, proton-sensing transcription factors will be characterised from studies of gene expression under chemically and optogenetically operated pH stimuli.
The definition of a cell’s fitness to survive at a particular microenvironment pH and its relationship with stemness remain unclear. Phenotyping pHi-gated subpopulations in terms of growth, stemness and tumourigenicity will define pH-fitness and its role in aggressiveness. In evolving to survive metabolism, cancer cells may acquire the ability to thrive in new niches.
Summary
Metabolism generates vast quantities of acid, which exerts broad-spectrum biological effects because protein protonation is a powerful post-translational modification. Regulation of intracellular pH (pHi) is therefore a homeostatic priority, but carefully orchestrated proton dynamics are a versatile signal.
Extracellular acidity is an established chemical signature of tumours and has recently been proposed to convey a signal that shapes the phenotypic landscape of cancer. Cancer’s genetic instability yields diversity in acid handling and signalling, forming a substrate for selection under acid-stress. This is a plausible mechanism for disease progression and an analogy can be drawn to experimentally-verified hypoxic selection.
Current models of acid handling in cancer are, however, based on population-averages of observations made at the cell level. This fails to appreciate diversity and the complexity inherent in tissues. We will produce a more complete understanding of acid handling that accounts for diffusive transport across tissue compartments and the role of the tumour stroma. A systems-approach of characterising pH-regulatory processes cell-by-cell will identify which components are liable to vary, and thus are a substrate for acid-driven somatic evolution.
The long-term effects of proton signals on gene expression have not been tested, despite evidence for proton-sensing transcription factors. To address the mechanism for adaptation to acid-stress, proton-sensing transcription factors will be characterised from studies of gene expression under chemically and optogenetically operated pH stimuli.
The definition of a cell’s fitness to survive at a particular microenvironment pH and its relationship with stemness remain unclear. Phenotyping pHi-gated subpopulations in terms of growth, stemness and tumourigenicity will define pH-fitness and its role in aggressiveness. In evolving to survive metabolism, cancer cells may acquire the ability to thrive in new niches.
Max ERC Funding
1 922 575 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym VERSUS
Project Violence Elites and Resilience in States Under Stress
Researcher (PI) Clionadh RALEIGH
Host Institution (HI) THE UNIVERSITY OF SUSSEX
Country United Kingdom
Call Details Consolidator Grant (CoG), SH2, ERC-2016-COG
Summary Political violence affects 2 billion citizens across the developing world. Conflict contributes to political decline, high corruption and poverty, poor social cohesion and low institutional trust. VERSUS represents a new direction in political, geographic and empirical subnational studies of conflict and governance. It determines how violence erupts from political processes in varied environments and examines how common internal and external shocks create new trajectories of governance, violence and potential for political resilience. It argues that political relationships between subnational elites and regimes incentivise political violence in developing states. Through a suite of multi-and-mixed methods including power mapping, extensive elite interviews, Bayesian spatial models and dynamic network innovations, VERSUS creates multiple real-time measures of power distribution across select African, Middle Eastern and Asian states for widespread research and policy use. It has five objectives: to advance a developing paradigm on subnational political architectures and environments over static institutionalism; to generate several measures of comparative political power distributions in developing states that capture the degree and depth of regime and elite relationships; to design and test scenarios to explain how, when and where violence erupts as a strategic function of architectures and environments; to develop and implement novel conflict ‘resilience’ tests of regimes, elites and vulnerable members of society in response to internal and external shocks. This creates a state’s ‘carrying capacity’ for shocks and violence; and finally, to collaborate with development practitioners and civil society to implement new standards for elite transparency, support for human rights and ‘good governance’ outcomes.
Summary
Political violence affects 2 billion citizens across the developing world. Conflict contributes to political decline, high corruption and poverty, poor social cohesion and low institutional trust. VERSUS represents a new direction in political, geographic and empirical subnational studies of conflict and governance. It determines how violence erupts from political processes in varied environments and examines how common internal and external shocks create new trajectories of governance, violence and potential for political resilience. It argues that political relationships between subnational elites and regimes incentivise political violence in developing states. Through a suite of multi-and-mixed methods including power mapping, extensive elite interviews, Bayesian spatial models and dynamic network innovations, VERSUS creates multiple real-time measures of power distribution across select African, Middle Eastern and Asian states for widespread research and policy use. It has five objectives: to advance a developing paradigm on subnational political architectures and environments over static institutionalism; to generate several measures of comparative political power distributions in developing states that capture the degree and depth of regime and elite relationships; to design and test scenarios to explain how, when and where violence erupts as a strategic function of architectures and environments; to develop and implement novel conflict ‘resilience’ tests of regimes, elites and vulnerable members of society in response to internal and external shocks. This creates a state’s ‘carrying capacity’ for shocks and violence; and finally, to collaborate with development practitioners and civil society to implement new standards for elite transparency, support for human rights and ‘good governance’ outcomes.
Max ERC Funding
1 999 390 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
