Furlong Group
Regulatory networks driving cell fate decisions: dissecting the logic
Figure 1: Transcription factor occupancy is sufficient to predict spatio-temporal cis-regulatory activity (Zinzen, Girardot, Gagneur et al., Nature 2009).
Figure 2: Dynamic enhancer occupancy reflects a temporal map of developmental progression (Wilczynski & Furlong, Mol Systems Biol, 2010).
Figure 3: The transcriptional network for early mesoderm development.
Previous and current research
Development is driven by the establishment of complex patterns of gene expression at precise times and spatial locations. Although a number of mechanisms fine-tune expression states, it is initially established through the integration of signalling and transcriptional networks converging on enhancer elements, or cis-regulatory modules (CRMs). Understanding how CRMs function is therefore central to understanding metazoan development and evolutionary change. Although there has been extensive progress in deciphering the function of individual regulatory elements, how these modules are integrated to regulate more global cis-regulatory networks remains a key challenge. Even in the extensively studied model organism, the Drosophila fruit fly, there are no predictive models for a transcriptional network leading to cell fate specification.
The main aim of our research is to understand how gene regulatory networks control development and how network perturbations lead to specific phenotypes. To address this we integrate functional genomic, genetic and computational approaches to make predictive models of developmental progression. We use Drosophila mesoderm specification into different muscle primordia as a model system. The relative simplicity of the fly mesoderm, in addition to the number of essential and conserved transcription factors already identified, make it an ideal model to understand cell fate decisions at a systems level.
Future projects and goals
Chromatin remodelling during cell fate decisions: We are currently developing a new system to investigate cell type specific changes in chromatin status using a number of genetic tools. This will allow changes in chromatin remodelling to be integrated with dynamic changes in transcription factor occupancy.
Evolution of cis-regulatory networks: To gain a better understanding of the core functional features of the transcriptional network driving mesoderm specification we will take advantage of the fact that all of the key transcription factors involved are highly conserved at both a sequence and phenotypic level. We plan to extend the global transcription network generated in Drosophila melanogaster to other Drosophilds and non-arthropod species.
Predictive models of embryonic development: We have recently demonstrated that using only information on combinatorial occupancy of transcription factors is sufficient to predict spatio-temporal cis-regulatory activity. We plan to extend this analysis from predicting CRM activity to predicting a gene’s expression. Our ultimate goal is to use this systems-level approach to make predictive models of embryonic development and the effect of genetic perturbations. Working in Drosophila allows us to readily test the predicted outcome of network perturbations on embryonic development.
10 years of the human genome
EMBL scientists mark a decade since the first draft human genome sequence. Click on the image to play.
Duration: 6 mins.