ayout 1 - EMBL Grenoble

EMBL-EBI
Genome-scale analysis of regulatory systems
Previous and current research
Cellular life must recognise and respond appropriately to diverse internal and external stimuli. By
ensuring the correct expression of specific genes at the appropriate times, the transcriptional regulatory
system plays a central role in controlling many biological processes: these range from cell
cycle progression and maintenance of intracellular metabolic and physiological balance, to cellular
differentiation and developmental time courses. Numerous diseases result from a breakdown
in the regulatory system and a third of human developmental disorders have been attributed to dysfunctional
transcription factors. Furthermore, alterations in the activity and regulatory specificity
of transcription factors are now established as major sources for species diversity and evolutionary
adaptation. Indeed, increased sophistication in the regulatory system appears to have been a
principal requirement for the emergence of metazoan life.
Much of our basic knowledge of transcription regulation has derived from molecular and genetic
investigations. In the past decade, the availability of genome sequences and development of new
laboratory techniques has generated (and continues to generate) information describing the function
and organisation of regulatory systems on an unprecedented scale. Genome-scale studies now
allow us to examine the regulatory system from a whole-organism perspective; on the other hand,
however, observations made with these data are often unexpected and appear to complicate our
view of gene expression control.
Nicholas
Luscombe
PhD 2000, University College
London.
Postdoctoral work at
Department of Molecular
Biophysics & Biochemistry,
Yale University.
Group leader at EMBL-EBI
since 2005.
Joint appointment with the
Gene Expression Unit.
This continued flood of biological data means that many interesting questions require the application
of computational methods to answer them. The strength of bioinformatics is its ability to uncover general principles providing global
descriptions of entire systems. Armed with these biological data we are now poised to achieve this.
Much of our work so far has focussed on the regulatory system in the yeast Saccharomyces cerevisiae. By integrating diverse data sources –
from genome sequence to the results of functional genomics experiments – we can study the regulatory system at a whole-organism level. We
have also expanded our interests to understanding regulation in enterobacteria and humans.
Our current projects include:
• examining how the metabolic system is controlled at multiple levels through the feedback activity of small molecules;
• analysing the repertoire, usage and cross-species conservation of transcription factors in the human genome;
• wet/dry collaborations to uncover the regulation governing
complex organismal behaviour;
• wet/dry collaborations to understand the epigenetic control
of dosage compensation in animals.
Future projects and goals
We will continue to develop new techniques to advance our understanding
of regulatory systems, and expand our approaches towards alternative
regulatory processes. A major focus continues to be our close
interactions with research groups performing genome-scale experiments.
A network representation displays the E. coli metabolic system. Nodes
represent small molecules and edges depict enzymatic reactions. The
reactions are coloured according to whether they are controlled
transcriptionally (blue), allosterically (cyan) or by both methods (green).
Allosteric feedback predominantly regulates anabolic pathways, whereas
transcriptional feedback controls both anabolic and catabolic pathways.
Selected references
Vaquerizas, J.M. et al. (2009). A census of transcription factors in the
human genome: function, expression and evolution. Nat. Rev.
Genet., 10, 252-63
Hancock, V. et al. (2008). Transcriptomics and adaptive genomics of
the asymptomatic bacteriuria Escherichia coli strain 83972. Mol.
Genet. Genomics, 1-12
Kind, J. et al. (2008). Genome-wide analysis reveals MOF as a key
regulator of dosage compensation and gene expression in
Drosophila. Cell, 133, 813-828
Seshasayee, A.S. et al. (2008). Principles of transcriptional regulation
and evolution of the metabolic system in E. coli. Genome Res., 19,
79-91.
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