Project acronym ERNBPTC
Project Expression regulatory networks: beyond promoters and transcription control
Researcher (PI) Yitzhak Pilpel
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary "Gene expression in living cells is a most intricate molecular process, occurring in stages, each of which is regulated by a diversity of mechanisms. Among the various stages leading to gene expression, only transcription is relatively well understood, thanks to Genomics and bioinformatics. In contrast to the vast amounts of genome-wide data and a growing understanding of the structure of networks controlling transcription, we still lack quantitative, genome-wide knowledge of the mechanisms underlying regulation of mRNA degradation and translation. Among the unknowns are the identity of the regulators, their kinetic modes of action, and their means of interaction with the sequence features that make-up their targets; how these target combine to produce a higher level ""grammar"" is also unknown. An important part of the project is dedicated to generating genome-wide experimental data that will form the basis for quantitative and more comprehensive analysis of gene expression. Specifically, the primary objectives of our proposed research plan are: 1) to advance our understanding of the transcriptome, by deciphering the code regulating mRNA decay 2) to break the code which controls protein translation efficiency 3) to understand how mRNA degradation and translation efficiency determine noise in protein expression levels. The proposed strategy is based on an innovative combination of computational prediction, synthetic gene design, and genome-wide data acquisition, all culminating in extensive data analysis, mathematical modeling and focused experiments. This highly challenging, multidisciplinary project is likely to greatly enhance our knowledge of the various modes by which organisms regulate expression of their genomes, how these regulatory mechanisms are interrelated, how they generate precise response to environmental challenges and how they have evolved over time."
Summary
"Gene expression in living cells is a most intricate molecular process, occurring in stages, each of which is regulated by a diversity of mechanisms. Among the various stages leading to gene expression, only transcription is relatively well understood, thanks to Genomics and bioinformatics. In contrast to the vast amounts of genome-wide data and a growing understanding of the structure of networks controlling transcription, we still lack quantitative, genome-wide knowledge of the mechanisms underlying regulation of mRNA degradation and translation. Among the unknowns are the identity of the regulators, their kinetic modes of action, and their means of interaction with the sequence features that make-up their targets; how these target combine to produce a higher level ""grammar"" is also unknown. An important part of the project is dedicated to generating genome-wide experimental data that will form the basis for quantitative and more comprehensive analysis of gene expression. Specifically, the primary objectives of our proposed research plan are: 1) to advance our understanding of the transcriptome, by deciphering the code regulating mRNA decay 2) to break the code which controls protein translation efficiency 3) to understand how mRNA degradation and translation efficiency determine noise in protein expression levels. The proposed strategy is based on an innovative combination of computational prediction, synthetic gene design, and genome-wide data acquisition, all culminating in extensive data analysis, mathematical modeling and focused experiments. This highly challenging, multidisciplinary project is likely to greatly enhance our knowledge of the various modes by which organisms regulate expression of their genomes, how these regulatory mechanisms are interrelated, how they generate precise response to environmental challenges and how they have evolved over time."
Max ERC Funding
1 320 000 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym INSPIRE
Project Interhemispheric stimulation promotes reading: two brains are better then one
Researcher (PI) Michal Lavidor
Host Institution (HI) BAR ILAN UNIVERSITY
Call Details Starting Grant (StG), SH3, ERC-2007-StG
Summary The ultimate goal of INSPIRE is to develop Transcranial Magnetic Stimulation (TMS)-based and training protocols that will improve semantic skills and creative thinking of healthy and impaired individuals by manipulating the balance between the hemispheres while they process language. Although ambitious and revolutionary, this goal is fundamental to conceptions of language processing and functional lateralization in the human brain. Specific objectives are: (1) To investigate how do semantic processes interact with creative thinking, particularly in the right hemisphere (RH). (2) To generate (reversible and temporary) localized functional impairment in healthy participants in order to specify the cortical areas involved in normal semantic processing. In particular, inhibitory TMS protocols will be used to investigate the role of the RH in processing remote associations, metaphors, sarcasm and subordinate meanings of ambiguous words. Complementary TMS-induced impairments are predicted for left hemisphere (LH) stimulation in language areas. (3) To improve RH semantic abilities and creative thinking by targeting excitatory TMS protocols at the regions of interest, and by enhancing the functioning of the homologue un-stimulated cortex with inhibitory protocols via disinhibition. (4) To improve RH semantic abilities and creative thinking by 'left' and 'right' hemisphere training. (5) To apply the research findings of objectives 1-4 above to aphasia, schizophrenia and RH brain damaged patients in order to improve their semantic skills. Prof. Lavidor is now moving back to Israel with her family after a long stay in the UK. The ERC support is requested for the re-establishment of an active and successful TMS lab in Israel, similar to the one Lavidor set up in the UK. The INSPIRE project, if funded, will allow her to build a new generation of inspired research students in her new lab, trained for excellence by Lavidor, who won the 2006 Marie Curie Excellence Award
Summary
The ultimate goal of INSPIRE is to develop Transcranial Magnetic Stimulation (TMS)-based and training protocols that will improve semantic skills and creative thinking of healthy and impaired individuals by manipulating the balance between the hemispheres while they process language. Although ambitious and revolutionary, this goal is fundamental to conceptions of language processing and functional lateralization in the human brain. Specific objectives are: (1) To investigate how do semantic processes interact with creative thinking, particularly in the right hemisphere (RH). (2) To generate (reversible and temporary) localized functional impairment in healthy participants in order to specify the cortical areas involved in normal semantic processing. In particular, inhibitory TMS protocols will be used to investigate the role of the RH in processing remote associations, metaphors, sarcasm and subordinate meanings of ambiguous words. Complementary TMS-induced impairments are predicted for left hemisphere (LH) stimulation in language areas. (3) To improve RH semantic abilities and creative thinking by targeting excitatory TMS protocols at the regions of interest, and by enhancing the functioning of the homologue un-stimulated cortex with inhibitory protocols via disinhibition. (4) To improve RH semantic abilities and creative thinking by 'left' and 'right' hemisphere training. (5) To apply the research findings of objectives 1-4 above to aphasia, schizophrenia and RH brain damaged patients in order to improve their semantic skills. Prof. Lavidor is now moving back to Israel with her family after a long stay in the UK. The ERC support is requested for the re-establishment of an active and successful TMS lab in Israel, similar to the one Lavidor set up in the UK. The INSPIRE project, if funded, will allow her to build a new generation of inspired research students in her new lab, trained for excellence by Lavidor, who won the 2006 Marie Curie Excellence Award
Max ERC Funding
638 400 €
Duration
Start date: 2008-10-01, End date: 2012-09-30
Project acronym SAMIT
Project Systems Analysis of Plant Metabolism through the Integration of Heterogeneous Data from Genetics, Informatics and Metabolomics
Researcher (PI) Asaph Aharoni
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary "The term METABOLISM describes all the chemical reactions and interactions that take place in a biological system. The regulation of metabolic pathways is constantly tuned in order to suit the needs of development and fitness. The main goal of the proposed research is to unravel networks of genes and proteins which coordinate the activity of metabolic pathways during plant development and stress response. In Phase I of the project, an infrastructure will be set-up that includes metabolite analyses technologies, a large tomato mutant population and a collection of tomato transcription factor genes. In Phase II, the population will be screened for novel mutants and genes associated with the research interests of the lab. The screens will include: a) visual screening, b) HTP, non laborious assays, c) non-targeted metabolite analysis for the detection of differential metabolites using LC-MS, and d) screening by a reverse genetic approach (from sequence to mutant) through transposon display. The collection of transcription factors will be used for rapid gene function analysis by means of Virus Induced Gene silencing (VIGS), and for the generation of a tomato transcription factors ""Interactome"" map. In Phase III, selected genes and mutants will be subjected to a detailed characterization including: a) the regulatory networks controlling fruit development, b) the regulation of metabolic pathways associated with plant surface metabolism and c) the regulation of the Isoprenoid pathway (including the glycoalkaloids and carotenoids). Data gathered from diverse platforms and screens will be integrated using computational tools to provide new knowledge on the genetic control of metabolic pathways that is currently very limited. This research addresses a major challenge, namely, the extensive acquisition of an heterogeneous set of data (genetic, gene expression, protein interaction and metabolic) and their integration to identify regulatory networks controlling plant metabolism."
Summary
"The term METABOLISM describes all the chemical reactions and interactions that take place in a biological system. The regulation of metabolic pathways is constantly tuned in order to suit the needs of development and fitness. The main goal of the proposed research is to unravel networks of genes and proteins which coordinate the activity of metabolic pathways during plant development and stress response. In Phase I of the project, an infrastructure will be set-up that includes metabolite analyses technologies, a large tomato mutant population and a collection of tomato transcription factor genes. In Phase II, the population will be screened for novel mutants and genes associated with the research interests of the lab. The screens will include: a) visual screening, b) HTP, non laborious assays, c) non-targeted metabolite analysis for the detection of differential metabolites using LC-MS, and d) screening by a reverse genetic approach (from sequence to mutant) through transposon display. The collection of transcription factors will be used for rapid gene function analysis by means of Virus Induced Gene silencing (VIGS), and for the generation of a tomato transcription factors ""Interactome"" map. In Phase III, selected genes and mutants will be subjected to a detailed characterization including: a) the regulatory networks controlling fruit development, b) the regulation of metabolic pathways associated with plant surface metabolism and c) the regulation of the Isoprenoid pathway (including the glycoalkaloids and carotenoids). Data gathered from diverse platforms and screens will be integrated using computational tools to provide new knowledge on the genetic control of metabolic pathways that is currently very limited. This research addresses a major challenge, namely, the extensive acquisition of an heterogeneous set of data (genetic, gene expression, protein interaction and metabolic) and their integration to identify regulatory networks controlling plant metabolism."
Max ERC Funding
1 009 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym TRANSCRIPTION_REG
Project A combined experimental and computational approach for quantitative and mechanistic understanding of transcriptional regulation
Researcher (PI) Eran Segal
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary The complex functions of a living cell are carried out through the coordinated activity of many genes. Since transcription is a key step in establishing such coordinated activity, much effort was devoted to its study, and tremendous progress was made in identifying many of the transcription factors and regulatory DNA elements involved in the regulation of specific systems. However, very few attempts were made at going beyond these phenomenological and qualitative descriptions. Consequently, we are far from a quantitative and predictive understanding of transcriptional regulation. Through this program, I aim to develop a mechanistic understanding of transcriptional regulation, and for the first time model the entire process. We wish to go much beyond identifying and qualitatively describing the involved components, and arrive at a quantitative understanding of how transcriptional programs are encoded in the DNA sequences. To this end, my team and I will first work to mechanistically understand various building blocks of the transcriptional system, including: mechanisms of activation and repression; binding cooperativity; binding competition; transcription factors and chromatin interplay; architectural features of promoters that are important for its function; and the transcription functions “computed” by promoters. Since existing data are clearly insufficient for addressing such questions, I have opened an experimental lab and began to assemble a multidisciplinary team of scientists whose expertise span the experimental biology, computer science, physics, statistics, and mathematics disciplines, that will work synergistically to generate the appropriate data, analyze it, and use it to construct and experimentally validate models for the above transcriptional building blocks. We will then integrate all the insights gained into unified and quantitative models that should significantly enhance our understanding of the mechanistic workings of transcriptional regulation.
Summary
The complex functions of a living cell are carried out through the coordinated activity of many genes. Since transcription is a key step in establishing such coordinated activity, much effort was devoted to its study, and tremendous progress was made in identifying many of the transcription factors and regulatory DNA elements involved in the regulation of specific systems. However, very few attempts were made at going beyond these phenomenological and qualitative descriptions. Consequently, we are far from a quantitative and predictive understanding of transcriptional regulation. Through this program, I aim to develop a mechanistic understanding of transcriptional regulation, and for the first time model the entire process. We wish to go much beyond identifying and qualitatively describing the involved components, and arrive at a quantitative understanding of how transcriptional programs are encoded in the DNA sequences. To this end, my team and I will first work to mechanistically understand various building blocks of the transcriptional system, including: mechanisms of activation and repression; binding cooperativity; binding competition; transcription factors and chromatin interplay; architectural features of promoters that are important for its function; and the transcription functions “computed” by promoters. Since existing data are clearly insufficient for addressing such questions, I have opened an experimental lab and began to assemble a multidisciplinary team of scientists whose expertise span the experimental biology, computer science, physics, statistics, and mathematics disciplines, that will work synergistically to generate the appropriate data, analyze it, and use it to construct and experimentally validate models for the above transcriptional building blocks. We will then integrate all the insights gained into unified and quantitative models that should significantly enhance our understanding of the mechanistic workings of transcriptional regulation.
Max ERC Funding
1 005 600 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
