Project: Modelling the genetic network controlling heart development using the model organism Drosophila melanogaster

ModHeart - Modelling the genetic network controlling heart development using the model organism Drosophila melanogaster. Developmental geneticists have unraveled the transcription factors and signaling pathways that control the formation of the cardiovascular system. These investigations have demonstrated a clear conservation of genetic control, from Drosophila to mammals. However, what these pathways control in terms of downstream gene networks and how they dynamically interact to control the diversification and the differentiation of cardiomyocytes remains largely unknown. A detailed understanding of these processes will provide essential insights into both normal and pathological heart development. Drosophila is an excellent model system to study gene regulatory networks involved in cardiac organogenesis: in addition to the wealth of genetic and genomic tools available, this ?simple? genetic model organism possesses a fluid pumping heart. Our objectives are to generate and integrate genome-wide qualitative and quantitative data to dissect the Gene Regulatory Network that dynamically controls the diversification and progressive differentiation of the cardiovascular system in Drosophila. More precisely, we will: ? Generate large scale data sets by ChIP-seq and transcriptomics to describe the direct transcriptional target genes and their enhancers (cis-regulatory control elements). ? Use computational tools to integrate and analyse the newly generated datasets with pre-existing public data (coming from large scale transcriptome, proteome, and interactome screens, as well as low-throughput data documented in scientific articles and public databases). ? Establish predictive, qualitative and quantitative dynamical models of the regulatory network controlling cardioblast cell specification and differentiation. ? Exploit the genetic tools (reporter gene essays, in situ hybridization, targeted overexpression mediated gain of function, dsRNA mediated gene function knockdown...) available in Drosophila to validate and refine theses models. ? Use computational tools to evaluate the conservation of the underlying regulatory circuits from insects to mammals. Overall, this project will contribute to building a systems-level view of Drosophila heart development and will benefit from the balanced expertise of its members..

Acronym	ModHeart
Project Results (after finalisation)	ModHeart consists in a systems biology approach to understand the genetic network driving cardiac organogenesis in Drosophila. The proposal concerned the use of cutting edge RNA-seq and ChiP-seq data acquisition, together with measures of transcription factor expression and activity to build sophisticated models of the underlying pattern of gene regulation during cardiomyocyte differentiation. Drosophila offers a number of critical advantages for this project, particularly the clarity and level of complexity of heart development and the opportunity to interrogate the models with existing mutant and variant strains and also the relative ease of introducing gene reporters. There were major challenges in this project, particularly the isolation of sufficient quantity and purity of sub-populations of cells for ChiP-seq and RNA-seq but we collectively solved them – allowing new tissue specific approaches to be set up and made available for the scientific community. The ultimate goal of the project is the generation of useful, logical and time-resolved qualitative models of the regulatory gene network specifying the development of the Drosophila heart. The discovery that dominant inherited transcription factor mutations can cause congenital heart defects in humans has brought direct medical relevance to the study of cardiac transcription factors in heart development. A detailed understanding of cardiac fate acquisition and differentiation processes thus provides important insights about normal and pathological heart development.
Network	ERASysBio+
Call	ERASysBio+-2008-01

Project partner

Number	Name	Role	Country
1	Aix-Marseille Université	Coordinator	France
2	Aix-Marseille Université	Partner	France
3	Genetic Reproduction & Development	Partner	France
4	European Molecular Biology Laboratory	Partner	Germany
5	European Molecular Biology Laboratory	Partner	Spain