Project acronym MIRTURN
Project Mechanisms of microRNA biogenesis and turnover
Researcher (PI) Helge Grosshans
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Call Details Starting Grant (StG), LS2, ERC-2009-StG
Summary MicroRNAs (miRNAs) are a novel class of genes, accounting for >1% of genes in a typical animal genome. They constitute an important layer of gene regulation that affects diverse processes such as cell differentiation, apoptosis, and metabolism. Despite such critical roles, deciphering the mechanism of action of miRNAs has been difficult, leading to multiple, partially contradictory, models of miRNA activity. Moreover, adding an additional layer of complexity, it is now emerging that miRNA activity is regulated by various mechanisms that we are only beginning to identify. Our objective is to understand how miRNAs are regulated under physiological conditions, in the roundworm Caenorhabditis elegans. We will focus on pathways of miRNA turnover, an issue of fundamental importance that has received little attention because miRNAs are widely held to be highly stable molecules. However, miRNA over-accumulation causes aberrant development and disease, prompting us to test rigorously whether degradation can antagonize miRNA activity and either identify the machinery involved, or confirm the dominance of other regulatory modalities, whose components we will identify. C. elegans is the organism in which miRNAs and many components of the miRNA machinery were discovered. However, previous studies emphasized genetics and cell biology approaches, limiting the degree of mechanistic insight that could be obtained. In addition to exploiting the traditional strengths of C. elegans, we will therefore develop and apply biochemical and genomic techniques to obtain a comprehensive understanding of miRNA regulation, enabling us to demonstrate both molecular mechanisms and physiological relevance. Given the importance of miRNAs in development and disease, identifying the regulators of these tiny gene regulators will be both of scientific interest and biomedical relevance.
Summary
MicroRNAs (miRNAs) are a novel class of genes, accounting for >1% of genes in a typical animal genome. They constitute an important layer of gene regulation that affects diverse processes such as cell differentiation, apoptosis, and metabolism. Despite such critical roles, deciphering the mechanism of action of miRNAs has been difficult, leading to multiple, partially contradictory, models of miRNA activity. Moreover, adding an additional layer of complexity, it is now emerging that miRNA activity is regulated by various mechanisms that we are only beginning to identify. Our objective is to understand how miRNAs are regulated under physiological conditions, in the roundworm Caenorhabditis elegans. We will focus on pathways of miRNA turnover, an issue of fundamental importance that has received little attention because miRNAs are widely held to be highly stable molecules. However, miRNA over-accumulation causes aberrant development and disease, prompting us to test rigorously whether degradation can antagonize miRNA activity and either identify the machinery involved, or confirm the dominance of other regulatory modalities, whose components we will identify. C. elegans is the organism in which miRNAs and many components of the miRNA machinery were discovered. However, previous studies emphasized genetics and cell biology approaches, limiting the degree of mechanistic insight that could be obtained. In addition to exploiting the traditional strengths of C. elegans, we will therefore develop and apply biochemical and genomic techniques to obtain a comprehensive understanding of miRNA regulation, enabling us to demonstrate both molecular mechanisms and physiological relevance. Given the importance of miRNAs in development and disease, identifying the regulators of these tiny gene regulators will be both of scientific interest and biomedical relevance.
Max ERC Funding
1 782 200 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym PTPSBDC
Project The role of protein-tyrosine phosphatases in breast development and cancer
Researcher (PI) Mohamed Bentires-Alj
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Call Details Starting Grant (StG), LS4, ERC-2009-StG
Summary Each year 1.1 million new cases of breast cancer will occur among women worldwide and 400,000 women will die from this disease. Although progress has been made in understanding breast tumor biology, most of the relevant molecules and pathways remain undefined. Their delineation is critical to a rational approach to breast cancer therapy. This proposal focuses on the role of the under-explored family of protein-tyrosine phosphatases (PTPs) in the normal and neoplastic breast. Virtually all cell signaling pathways are modulated by reversible protein tyrosine phosphorylation, which is regulated by two classes of enzymes: protein-tyrosine kinases (PTKs) and PTPs. Not surprisingly, tyrosine phosphorylation has an important role in breast development and cancer. Whereas the role of specific PTKs, like the HER2 receptor, in breast cancer is well studied, almost nothing is known about the function of specific PTPs in this disease. Our preliminary data suggest that PTP1B has an important role in breast differentiation and that both PTP1B and SHP2 play positive roles in breast cancer. The two predominant goals of this proposal are: First, to delineate the role of PTP1B and other PTPs in normal breast development and differentiation; second, to address the roles of PTP1B and other PTPs in the maintenance of breast cancer and metastasis and to assess their merits as drug targets. These studies not only use state-of-the-art ex vivo and in vivo models for studying breast pathophysiology, but also cross the boundaries between the developmental and cancer research fields and between basic science and clinical applications. Our research should ultimately lead to the rational design of targeted therapies that will improve the clinical management of patients with breast cancer.
Summary
Each year 1.1 million new cases of breast cancer will occur among women worldwide and 400,000 women will die from this disease. Although progress has been made in understanding breast tumor biology, most of the relevant molecules and pathways remain undefined. Their delineation is critical to a rational approach to breast cancer therapy. This proposal focuses on the role of the under-explored family of protein-tyrosine phosphatases (PTPs) in the normal and neoplastic breast. Virtually all cell signaling pathways are modulated by reversible protein tyrosine phosphorylation, which is regulated by two classes of enzymes: protein-tyrosine kinases (PTKs) and PTPs. Not surprisingly, tyrosine phosphorylation has an important role in breast development and cancer. Whereas the role of specific PTKs, like the HER2 receptor, in breast cancer is well studied, almost nothing is known about the function of specific PTPs in this disease. Our preliminary data suggest that PTP1B has an important role in breast differentiation and that both PTP1B and SHP2 play positive roles in breast cancer. The two predominant goals of this proposal are: First, to delineate the role of PTP1B and other PTPs in normal breast development and differentiation; second, to address the roles of PTP1B and other PTPs in the maintenance of breast cancer and metastasis and to assess their merits as drug targets. These studies not only use state-of-the-art ex vivo and in vivo models for studying breast pathophysiology, but also cross the boundaries between the developmental and cancer research fields and between basic science and clinical applications. Our research should ultimately lead to the rational design of targeted therapies that will improve the clinical management of patients with breast cancer.
Max ERC Funding
1 571 365 €
Duration
Start date: 2010-02-01, End date: 2015-01-31
Project acronym RECONMET
Project Reconstruction of methane flux from lakes: development and application of a new approach
Researcher (PI) Oliver Heiri
Host Institution (HI) UNIVERSITAET BERN
Call Details Starting Grant (StG), PE10, ERC-2009-StG
Summary Reconstruction of methane flux from lakes: development and application of a new approach
Summary
Reconstruction of methane flux from lakes: development and application of a new approach
Max ERC Funding
1 554 000 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym SEXGENTRANSEVOLUTION
Project Sex-biased genome and transcriptome evolution in mammals
Researcher (PI) Henrik Kaessmann
Host Institution (HI) UNIVERSITE DE LAUSANNE
Call Details Starting Grant (StG), LS2, ERC-2009-StG
Summary Mammalian males and females have many phenotypic differences. These differences, collectively referred to as sexual dimorphism, are the consequence of natural and sexual selection for phenotypic traits that affect the fitness of each sex and are encoded in the genome. Part of the underlying genomic differences between the sexes are found on sex specific (the Y) or sex biased chromosomes (the X), while many sexually dimorphic traits probably result from autosomal gene expression differences in sex specific or somatic tissues. However, the origin and evolution of sex-biased genes in mammals has not been studied in detail. I propose to generate the first detailed qualitative and quantitative transcriptome data using next generation sequencing technologies for a unique collection of germline and somatic tissues from representatives of all major mammalian lineages: placental mammals, marsupials, and the egg-laying monotremes. Together with detailed transcriptome data from birds (the evolutionary sister lineage), complementary experiments (e.g. methylome analyses), and available genomic resources from these species, these unprecedented data will allow an integrated analysis of the origin and functional evolution of mammalian sex chromosomes, the emergence of new sex biased genes, and the evolution of gene expression in germline versus somatic tissues in mammals at large. The proposed work will thus substantially increase our power to understand how mammalian genomes evolved the capacity to produce such pronounced sexually dimorphic traits. Beyond research pertaining to sex biased genome evolution, our data will represent a unique resource for future investigations of mammalian gene functions and serve as a basis for exploring the evolution of other mammal specific phenotypes.
Summary
Mammalian males and females have many phenotypic differences. These differences, collectively referred to as sexual dimorphism, are the consequence of natural and sexual selection for phenotypic traits that affect the fitness of each sex and are encoded in the genome. Part of the underlying genomic differences between the sexes are found on sex specific (the Y) or sex biased chromosomes (the X), while many sexually dimorphic traits probably result from autosomal gene expression differences in sex specific or somatic tissues. However, the origin and evolution of sex-biased genes in mammals has not been studied in detail. I propose to generate the first detailed qualitative and quantitative transcriptome data using next generation sequencing technologies for a unique collection of germline and somatic tissues from representatives of all major mammalian lineages: placental mammals, marsupials, and the egg-laying monotremes. Together with detailed transcriptome data from birds (the evolutionary sister lineage), complementary experiments (e.g. methylome analyses), and available genomic resources from these species, these unprecedented data will allow an integrated analysis of the origin and functional evolution of mammalian sex chromosomes, the emergence of new sex biased genes, and the evolution of gene expression in germline versus somatic tissues in mammals at large. The proposed work will thus substantially increase our power to understand how mammalian genomes evolved the capacity to produce such pronounced sexually dimorphic traits. Beyond research pertaining to sex biased genome evolution, our data will represent a unique resource for future investigations of mammalian gene functions and serve as a basis for exploring the evolution of other mammal specific phenotypes.
Max ERC Funding
1 901 522 €
Duration
Start date: 2010-02-01, End date: 2015-01-31
Project acronym UMICIS
Project Uncultivated Microbes In Situ - a Computational Biology Approach to Determine Molecular Capabilities and Ecological Roles
Researcher (PI) Christian Von Mering
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Starting Grant (StG), LS2, ERC-2009-StG
Summary Most of nature s biodiversity, and many potentially useful metabolic capabilities, remain hidden among the vast numbers of uncharacterized environmental microbes. Because cultivation is still not possible for most of these microbes, cultivation-independent molecular techniques such as polymerase chain reaction (PCR), fluorescent in situ hybridization (FISH), or shotgun DNA sequencing have been used in order to study their function and ecology in their natural habitats. However, none of the above techniques have so far been sufficient for any systematic assignment of molecular functions to distinct microbial lineages. Thus, most of the molecular ecology of natural microbes remains elusive. Here, we propose a computational meta-analysis and synthesis of existing and newly generated molecular sequence data sampled directly from the environment combining DNA sequencing data (metagenomics), and proteome expression data (metaproteomics). This analysis will be coupled to computational modelling of genome content evolution at the community level. We will aim to assess how gene repertoires of microbial communities, and their taxonomic compositions, change across distinct environments, in response to changed conditions, and through time. We plan to address fundamental questions in microbial ecology, including the extent of cooperation among members of the communities, stability of community composition at evolutionary timescales, the importance of lateral gene transfers, the extent of functional adaptation/regulation in situ, and whether gene occurrence and expression patterns are diagnostic of community functions and ecological status.
Summary
Most of nature s biodiversity, and many potentially useful metabolic capabilities, remain hidden among the vast numbers of uncharacterized environmental microbes. Because cultivation is still not possible for most of these microbes, cultivation-independent molecular techniques such as polymerase chain reaction (PCR), fluorescent in situ hybridization (FISH), or shotgun DNA sequencing have been used in order to study their function and ecology in their natural habitats. However, none of the above techniques have so far been sufficient for any systematic assignment of molecular functions to distinct microbial lineages. Thus, most of the molecular ecology of natural microbes remains elusive. Here, we propose a computational meta-analysis and synthesis of existing and newly generated molecular sequence data sampled directly from the environment combining DNA sequencing data (metagenomics), and proteome expression data (metaproteomics). This analysis will be coupled to computational modelling of genome content evolution at the community level. We will aim to assess how gene repertoires of microbial communities, and their taxonomic compositions, change across distinct environments, in response to changed conditions, and through time. We plan to address fundamental questions in microbial ecology, including the extent of cooperation among members of the communities, stability of community composition at evolutionary timescales, the importance of lateral gene transfers, the extent of functional adaptation/regulation in situ, and whether gene occurrence and expression patterns are diagnostic of community functions and ecological status.
Max ERC Funding
1 129 800 €
Duration
Start date: 2010-02-01, End date: 2016-01-31
