Project acronym REGULATORY GENOMICS
Project Regulatory Genomics in Drosophila
Researcher (PI) Alexander Stark
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS2, ERC-2009-StG
Summary A major goal of biology is to explain how gene regulatory information is encoded by the genome. To date, we cannot decipher this regulatory code, despite the cells ability to read it in natural and artificial sequence contexts, and in contrast to our detailed understanding of the genetic code, which allows us to seamlessly translate DNA into protein sequences. Here, I propose a regulatory genomics approach in Drosophila with three specific objectives: First, we will determine the sequence basis of how individual Hox transcription factors (Scr, Antp, Ubx, abd-A, Abd-B) and factors downstream of signalling pathways (Sd, pan, ci, Su(H), pnt, Stat93E, Mad, Smox, CrebA) regulate different genes in different tissues. We will perform tissue-specific ChIP-Seq and measure gene expression in mesoderm/muscle, epidermis, and neurons, and explain common and tissue-specific targets by their sequences. Second, we will determine requirements for enhancer function in several different cell-types, by performing an exhaustive and unbiased enhancer screen and computationally analyzing the sequences. Third, we will build a computational model to extract general rules from objectives 1 & 2, learn the regulatory codes, and make specific predictions. We will validate our model using cross-validation and predictions with unrelated sequence (e.g. from yeast), and will finally use it to design enhancers that are active in specific cell-types or combinations of cell-types. Our combination of experimental and computational methods makes us confident that we will make major contributions to the understanding of gene regulation in the fly. We anticipate that we will learn general principles, which will hold across tissues and animals, and might ultimately lead to the general regulatory code.
Summary
A major goal of biology is to explain how gene regulatory information is encoded by the genome. To date, we cannot decipher this regulatory code, despite the cells ability to read it in natural and artificial sequence contexts, and in contrast to our detailed understanding of the genetic code, which allows us to seamlessly translate DNA into protein sequences. Here, I propose a regulatory genomics approach in Drosophila with three specific objectives: First, we will determine the sequence basis of how individual Hox transcription factors (Scr, Antp, Ubx, abd-A, Abd-B) and factors downstream of signalling pathways (Sd, pan, ci, Su(H), pnt, Stat93E, Mad, Smox, CrebA) regulate different genes in different tissues. We will perform tissue-specific ChIP-Seq and measure gene expression in mesoderm/muscle, epidermis, and neurons, and explain common and tissue-specific targets by their sequences. Second, we will determine requirements for enhancer function in several different cell-types, by performing an exhaustive and unbiased enhancer screen and computationally analyzing the sequences. Third, we will build a computational model to extract general rules from objectives 1 & 2, learn the regulatory codes, and make specific predictions. We will validate our model using cross-validation and predictions with unrelated sequence (e.g. from yeast), and will finally use it to design enhancers that are active in specific cell-types or combinations of cell-types. Our combination of experimental and computational methods makes us confident that we will make major contributions to the understanding of gene regulation in the fly. We anticipate that we will learn general principles, which will hold across tissues and animals, and might ultimately lead to the general regulatory code.
Max ERC Funding
1 794 400 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym TMIHCV
Project Microfabrication-Based Rational Design of Transcriptional-Metabolic Intervention for the Treatment of Hepatitis C Virus (HCV) Infection
Researcher (PI) Yaakov Nahmias
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS9, ERC-2009-StG
Summary Hepatitis C Virus (HCV) infection affects over 3% of the world population and is the leading cause of chronic liver disease worldwide. Current treatments are effective in only 50% of the cases and associated with significant side effects. Therefore, there is a pressing need for the development of alternative treatments. Recently, our group and others demonstrated that the HCV lifecycle is critically dependent on host lipid metabolism. In this context, we demonstrated that the grapefruit flavonoid naringenin blocks HCV production through PPAR± and LXR±, transcriptional regulators of hepatic lipid metabolism. While these results are promising, our ability to rationally control metabolic pathways in infected cells is limited due to an incomplete understanding of the regulation of hepatic metabolism by its underlying transcriptional network. This project aims to develop a comprehensive model of hepatic metabolism by integrating metabolic fluxes with transcriptional regulation enabling the rational design of transcriptional-interventions which will minimize HCV replication and release. Our approach is to develop two microfabricated platforms that will enable high-throughput data acquisition and a human-relevant screening. One component is the Transcriptional Activity Array (TAA), a microdevice for the high-throughput temporal acquisition of transcriptional activity data. The second is the Portal Circulation Platform (PCP) which integrates intestinal absorption module with a liver metabolism compartment enabling the high-throughput human-relevant screening of treatments as a substitute to animal experiments. This work will lead to the development of novel drug combinations for the treatment of HCV infection and impact the treatment of diabetes, obesity, and dyslipidemia.
Summary
Hepatitis C Virus (HCV) infection affects over 3% of the world population and is the leading cause of chronic liver disease worldwide. Current treatments are effective in only 50% of the cases and associated with significant side effects. Therefore, there is a pressing need for the development of alternative treatments. Recently, our group and others demonstrated that the HCV lifecycle is critically dependent on host lipid metabolism. In this context, we demonstrated that the grapefruit flavonoid naringenin blocks HCV production through PPAR± and LXR±, transcriptional regulators of hepatic lipid metabolism. While these results are promising, our ability to rationally control metabolic pathways in infected cells is limited due to an incomplete understanding of the regulation of hepatic metabolism by its underlying transcriptional network. This project aims to develop a comprehensive model of hepatic metabolism by integrating metabolic fluxes with transcriptional regulation enabling the rational design of transcriptional-interventions which will minimize HCV replication and release. Our approach is to develop two microfabricated platforms that will enable high-throughput data acquisition and a human-relevant screening. One component is the Transcriptional Activity Array (TAA), a microdevice for the high-throughput temporal acquisition of transcriptional activity data. The second is the Portal Circulation Platform (PCP) which integrates intestinal absorption module with a liver metabolism compartment enabling the high-throughput human-relevant screening of treatments as a substitute to animal experiments. This work will lead to the development of novel drug combinations for the treatment of HCV infection and impact the treatment of diabetes, obesity, and dyslipidemia.
Max ERC Funding
1 994 395 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
