ayout 1 - EMBL Grenoble

EMBL Research at a Glance 2009
Gene regulatory networks: Dissecting the logic
Eileen Furlong
PhD 1996, University College
Dublin.
Postdoctoral research at
Stanford University.
Group leader at EMBL since
September 2002.
Senior scientist and joint Unit
Coordinator of Gene
Expression Unit since 2009.
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 gene expression, it is
initially established through the integration of signalling and transcriptional networks converging
on enhancer elements, or cis-regulatory modules (CRMs). CRMs serve as regulatory circuits that
integrate diverse transcriptional inputs leading to a specific spatio-temporal output of expression.
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 CRMs, 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 are particularly interested in the topology and function of developmental
networks at a global level.
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
We have constructed a comprehensive cis-regulatory network during
consecutive stages of development, elucidating the combinatorial
binding and temporal occupancy of thousand of cis-regulatory
modules, which we are currently using to understand differ aspects
of gene expression. Our future work will involve extending this network
to other species to study the evolution of cis-regulatory networks
at a genome-wide scale. We are also generating genetic tools
to allow us investigate changes in chromatin remodelling
during cell fate decisions. Our ultimate
goal is to use this systems-level approach
to make predictive models of embryonic development
and the effect of genetic perturbations.
Working with Drosophila allows us to readily test
all predictions on network perturbations during
embryonic development.
Figure 1: Genome-wide map of enhancer occupancy
Figure 2: The transcriptional network for
early mesoderm development
Selected references
Liu, Y.H., Jakobsen, J.S., Valentin, G., Amarantos, I., Gilmour, D.T. &
Furlong, E.E. (2009). A systematic analysis of Tinman function
reveals Eya and JAK-STAT signaling as essential regulators of
muscle development. Dev. Cell, 16, 280-91
Bonn, S. & Furlong, E.E. (2008). cis-Regulatory networks during
development: a view of Drosophila. Curr Opin Genet Dev., 18, 513-
20
32
Jakobsen, J.S., Braun, M., Astorga, J., Gustafson, E.H., Sandmann,
T., Karzynski, M., Carlsson, P. & Furlong, E.E. (2007). Temporal
ChIP-on-chip reveals Biniou as a universal regulator of the visceral
muscle transcriptional network. Genes Dev., 21, 28-60
Sandmann, T., Girardot, C., Brehme, M., Tongprasit, W., Stolc, V. &
Furlong, E.E. (2007). A core transcriptional network for early
mesoderm development in Drosophila melanogaster. Genes Dev.,
21, 36-9