Elucidating Transcriptional Regulatory Networks in Drosophila Embryonic Heart Development

Project: Research

Investigators

  • Anton Aboukhalil (PI)

Description

Heart malformations are the most widespread class of congenital defects; yet, we still do not fully understand their underlying mechanisms. Cardiogenesis is orchestrated by extensive transcriptional networks of groups of co-regulatory transcription factors (cis-regulatory codes) and their target DNA cis-regulatory modules (CRMs). These networks direct cell-type specific gene expression and cell fate. Thus, elucidating the regulatory networks that guide heart formation will provide us with a better understanding of its developmental program and its associated congenital defects.This proposal specifically addresses the challenges of delineating the unknown transcriptional regulatory networks in the Drosophila embryonic heart, a highly conserved model with lack of functional redundancy, and which affords unique genetic manipulations unfeasible in mammalian systems. This proposal is of computational nature, but is based on a close dialog with experimental collaborators, and is organized around three aims.In Aim 1, I propose to identify the cis-regulatory codes and their target CRMs which:(a) confer specificity of expression to individual cardial and pericardial cell types, the two main populations of the Drosophila embryonic heart(b) regulate the progression of heart tube closureThe gene set enrichment based algorithm Lever and PhylCRM will be applied to expedite the elucidation of the transcriptional regulatory networks. In Aim 2, I propose five strategies to expand the Lever algorithm to efficiently allow exploratory searches of cis-regulatory codes using large collections of motifs. This goal is currently intractable due to the combinatorial explosion of hypotheses tested, loss of statistical power, and exorbitant solution time. Finally, in Aim 3, I propose to systematically exploit in vivo data from ChIP-Seq (chromatin immunoprecipitation followed by massive parallel sequencing) experiments of TFs and chromatin marks to help the discovery of cardiac-specific regulatory codes, enhancers, and networks.Altogether, these studies are expected to reveal novel attributes of transcriptional networks in general and the unique codes that direct gene expression programs in specific cell types within the developing Drosophila heart. In the long term, I hope to better understand the conserved human cardiogenic networks and ultimately provide potential targets for the development of molecular-based diagnostics and therapies for congenital heart disease
Award amount$42,000.00
Award date07/01/2009
Program typePredoctoral Fellowship
Award ID09PRE2060465
Effective start/end date07/01/200906/30/2011
StatusFinished