Project acronym CHROMOREPAIR
Project Genome Maintenance in the Context of Chromatin
Researcher (PI) Oscar Fernández-Capetillo Ruiz
Host Institution (HI) FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary With the availability of the essentially complete sequence of the human genome, as well as a rapid development of massive sequencing techniques, the research efforts to understand genetics and disease from a cis standpoint will soon reach an endpoint. However, our emerging knowledge of gene regulation networks reveals that epigenetic regulation of the hereditary information plays crucial roles in various biological events through its influence on processes such as transcription, DNA replication and chromosome architecture. Another scenario in which the control of chromatin structure is crucial is the repair of lesions in genomic DNA. There is mounting evidence, particularly from model organisms such as Saccharomyces cerevisiae, that histone modifying enzymes (acetylases, deacetylases, kinases, …) are essential components of the machinery that maintains genome integrity and thereby guards against cancer, degenerative diseases and ageing. However, little is known about the specific “code” of histone tail modifications that coordinate DNA repair, and the impact that an aberrant “histone code” may have on human health. In CHROMOREPAIR we will systematically analyze the chromatin remodelling process that undergoes at DNA lesions and evaluate the impact that chromatin alterations have on the access, signaling and repair of DNA damage. Furthermore, we propose to translate our in vitro knowledge to the development of mouse models that help us evaluate how modulation of chromatin status impinges on genome maintenance and therefore on cancer and aging. As a provocative line of research and based on our preliminary data, we propose that certain chromatin alterations could not only impair but also in some cases promote a more robust response to DNA breaks, which could be a novel and not yet explored way to potentiate the elimination of pre-cancerous cells.
Summary
With the availability of the essentially complete sequence of the human genome, as well as a rapid development of massive sequencing techniques, the research efforts to understand genetics and disease from a cis standpoint will soon reach an endpoint. However, our emerging knowledge of gene regulation networks reveals that epigenetic regulation of the hereditary information plays crucial roles in various biological events through its influence on processes such as transcription, DNA replication and chromosome architecture. Another scenario in which the control of chromatin structure is crucial is the repair of lesions in genomic DNA. There is mounting evidence, particularly from model organisms such as Saccharomyces cerevisiae, that histone modifying enzymes (acetylases, deacetylases, kinases, …) are essential components of the machinery that maintains genome integrity and thereby guards against cancer, degenerative diseases and ageing. However, little is known about the specific “code” of histone tail modifications that coordinate DNA repair, and the impact that an aberrant “histone code” may have on human health. In CHROMOREPAIR we will systematically analyze the chromatin remodelling process that undergoes at DNA lesions and evaluate the impact that chromatin alterations have on the access, signaling and repair of DNA damage. Furthermore, we propose to translate our in vitro knowledge to the development of mouse models that help us evaluate how modulation of chromatin status impinges on genome maintenance and therefore on cancer and aging. As a provocative line of research and based on our preliminary data, we propose that certain chromatin alterations could not only impair but also in some cases promote a more robust response to DNA breaks, which could be a novel and not yet explored way to potentiate the elimination of pre-cancerous cells.
Max ERC Funding
948 426 €
Duration
Start date: 2008-12-01, End date: 2013-11-30
Project acronym EXTREMEPHYSICS
Project The slowest accreting neutron stars and black holes: New ways to probe fundamental physics
Researcher (PI) Rudi Wijnands
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Call Details Starting Grant (StG), PE7, ERC-2007-StG
Summary Very recently, a new class of sub-luminous accreting neutron stars and black holes has been identified. I propose to use these objects to probe the extreme physical processes which are associated with such compact stars. Just as with their better known brighter cousins, studying them when they are actively accreting and when they are in their quiescent states will give us clues about the behavior of ultra-dense matter in neutron stars and the way neutron-star magnetic fields decay due to the accretion of matter. However, given that these new systems behave differently, I expect to derive from their study a novel perspective which will gain in value even further when contrasted with our current knowledge. I further believe their study will allow me to significantly strengthen the observational proof for the presence of event horizons in black holes. The uncommon nature of these systems suggests that they are very unusual outcomes of binary evolution, and I expect this will also provide us with a different set of clues than we have had until now about the formation of binaries which harbor compact stars. These objects have only recently been discovered, both because we did not have the sensitivity to see them, and because we did not know how to optimize our searches to find them. Current instruments finally have reached the necessary sensitivity. I propose new approaches to find and study these sub-luminous systems using these X-ray and radio instruments in combination with multi-wavelength studies. I expect to find these systems in greater numbers than before, allowing systematic studies of their properties which in turn will provide the ingredients needed to investigate the fundamental physics associated with neutron stars and black holes and serve as input for my proposed theoretical study into binary evolution.
Summary
Very recently, a new class of sub-luminous accreting neutron stars and black holes has been identified. I propose to use these objects to probe the extreme physical processes which are associated with such compact stars. Just as with their better known brighter cousins, studying them when they are actively accreting and when they are in their quiescent states will give us clues about the behavior of ultra-dense matter in neutron stars and the way neutron-star magnetic fields decay due to the accretion of matter. However, given that these new systems behave differently, I expect to derive from their study a novel perspective which will gain in value even further when contrasted with our current knowledge. I further believe their study will allow me to significantly strengthen the observational proof for the presence of event horizons in black holes. The uncommon nature of these systems suggests that they are very unusual outcomes of binary evolution, and I expect this will also provide us with a different set of clues than we have had until now about the formation of binaries which harbor compact stars. These objects have only recently been discovered, both because we did not have the sensitivity to see them, and because we did not know how to optimize our searches to find them. Current instruments finally have reached the necessary sensitivity. I propose new approaches to find and study these sub-luminous systems using these X-ray and radio instruments in combination with multi-wavelength studies. I expect to find these systems in greater numbers than before, allowing systematic studies of their properties which in turn will provide the ingredients needed to investigate the fundamental physics associated with neutron stars and black holes and serve as input for my proposed theoretical study into binary evolution.
Max ERC Funding
500 000 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym MIREG
Project Identifying novel regulatory mechanisms of miRNA functions
Researcher (PI) Reuven Agami
Host Institution (HI) STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary microRNAs (miRNAs) are master regulators of gene expression capable of defining and altering cell identity. Because of their potency, small size, simple mode of action (target recognition through a Watson-Crick type of base pairing) and the possibility to inhibit them in vivo, miRNAs are valuable therapeutic targets. Recently, we have used novel functional-genetic screening approaches and identified the miR-372, 373 and 520, as well as the miR-221&222 family as cancerous miRNAs. These miRNAs are oncogenes, as they are deregulated in specific types of cancers, target tumor suppressors and their inhibition reverts cancerous phenotypes. However, at present almost nothing is known about the mechanisms governing the expression and function of these, as well as many other, oncogenic miRNAs. Here, I propose experiments to identify and characterize factors affecting the activity of oncogenic miRNAs using an array of molecular and genetic tools. Our preliminary results indicate the existence of novel regulators and mechanisms of miRNA activity. We therefore believe that the information collected here not only will lead to a better understanding of miRNA functions, but will also identify novel modes of manipulating miRNA activity in human disease.
Summary
microRNAs (miRNAs) are master regulators of gene expression capable of defining and altering cell identity. Because of their potency, small size, simple mode of action (target recognition through a Watson-Crick type of base pairing) and the possibility to inhibit them in vivo, miRNAs are valuable therapeutic targets. Recently, we have used novel functional-genetic screening approaches and identified the miR-372, 373 and 520, as well as the miR-221&222 family as cancerous miRNAs. These miRNAs are oncogenes, as they are deregulated in specific types of cancers, target tumor suppressors and their inhibition reverts cancerous phenotypes. However, at present almost nothing is known about the mechanisms governing the expression and function of these, as well as many other, oncogenic miRNAs. Here, I propose experiments to identify and characterize factors affecting the activity of oncogenic miRNAs using an array of molecular and genetic tools. Our preliminary results indicate the existence of novel regulators and mechanisms of miRNA activity. We therefore believe that the information collected here not only will lead to a better understanding of miRNA functions, but will also identify novel modes of manipulating miRNA activity in human disease.
Max ERC Funding
1 349 760 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym MULTICELLGENOME
Project A comparative genomic analysis into the origin of metazoan multicellularity
Researcher (PI) Inaki Ruiz Trillo
Host Institution (HI) UNIVERSITAT DE BARCELONA
Call Details Starting Grant (StG), LS5, ERC-2007-StG
Summary The emergence of multicellular organisms from single-celled ancestors is one of the most profound evolutionary steps in life’s history. However, and despite its importance, little is known about this pivotal evolutionary event. Interestingly, the emergence of multicellular organisms has occurred several times independently within the eukaryotes, such as in animals, fungi and plants. In this context, the super-group known as the Opisthokonts offers a unique evolutionary window to investigate the unicell-to-multicell transition because it comprises two multicellular eukaryotic kingdoms (Animals and Fungi) and several single-celled lineages. The goal of this project is to perform a comparative genomic analysis to further investigate into the origin of multicellularity within metazoans. Although genomic and functional studies are currently being performed in basal and derived metazoans, among the animal unicellular ancestors, choanoflagellates remain the only lineage to be extensively studied. This project aims to fill this gap by providing a genomic and molecular investigation into two additional unicellular lineages recently shown to be closely related to animals: Capsaspora owczarzaki and the ichthyosporean Sphaeroforma arctica. Thus, the specific goals of this project are: 1) to analyze the complete genome sequence of the unicellular opisthokonts Capsaspora and Sphaeroforma; and 2) to launch a new functional genomics platform of both Capsaspora and Sphaeroforma, in where to elucidate the “ancestral function” of genes relevant to multicellularity. A broad range of researchers (including the “evo-devo” community, eukaryotic microbiologists and molecular evolutionists) will benefit from the data generated within this project. Surely, this research will not only largely improve our understanding of a major biological question (the origin/s of multicellularity) but will also provide an evolutionary insight into the evolution of key proteins relevant to human health.
Summary
The emergence of multicellular organisms from single-celled ancestors is one of the most profound evolutionary steps in life’s history. However, and despite its importance, little is known about this pivotal evolutionary event. Interestingly, the emergence of multicellular organisms has occurred several times independently within the eukaryotes, such as in animals, fungi and plants. In this context, the super-group known as the Opisthokonts offers a unique evolutionary window to investigate the unicell-to-multicell transition because it comprises two multicellular eukaryotic kingdoms (Animals and Fungi) and several single-celled lineages. The goal of this project is to perform a comparative genomic analysis to further investigate into the origin of multicellularity within metazoans. Although genomic and functional studies are currently being performed in basal and derived metazoans, among the animal unicellular ancestors, choanoflagellates remain the only lineage to be extensively studied. This project aims to fill this gap by providing a genomic and molecular investigation into two additional unicellular lineages recently shown to be closely related to animals: Capsaspora owczarzaki and the ichthyosporean Sphaeroforma arctica. Thus, the specific goals of this project are: 1) to analyze the complete genome sequence of the unicellular opisthokonts Capsaspora and Sphaeroforma; and 2) to launch a new functional genomics platform of both Capsaspora and Sphaeroforma, in where to elucidate the “ancestral function” of genes relevant to multicellularity. A broad range of researchers (including the “evo-devo” community, eukaryotic microbiologists and molecular evolutionists) will benefit from the data generated within this project. Surely, this research will not only largely improve our understanding of a major biological question (the origin/s of multicellularity) but will also provide an evolutionary insight into the evolution of key proteins relevant to human health.
Max ERC Funding
1 211 275 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
