Nicholas Luscombe: Projects

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 (TFs). Furthermore, alterations in the activity and regulatory specificity of TFs are now established as major sources for species diversity and evolutionary adaptation. Indeed, increased sophistication of the regulatory system appears to have been a principal requirement for the emergence of metazoan life.

Much of our basic knowledge of transcriptional regulation has derived from molecular biological and genetic investigation. In the past decade, the availability of genome sequences and development of new laboratory techniques have generated (and continue to generate) information describing the function and organisation of regulatory systems on an unprecedented scale. Genomic studies now allow us to examine regulatory systems from a whole-organism perspective; on the other hand however, many observations made with these data are unexpected and appear to complicate our view of gene expression control.

The continued flood of biological data means that many interesting questions require the application of computational methods to answer them. The combination of computational biology and genomics enables us to uncover general principles that apply to many different biological systems; any unique features of individual systems can then be understood within this broader context.

The Computational Biology Group applies computational and genomic methods to answer three main questions:

  1. How is gene expression regulated?
  2. How do these mechanisms control interesting biological behaviours?
  3. How does gene regulation interact with evolutionary processes?

Much of our work until now has been purely computational, either analysing publicly available data or in collaboration with experimental laboratories performing functional genomic investigations.

Research highlights

Prevention of aberrant exonisation of Alu elements

In collaboration with Jernej Ule's laboratory (University College London) we developed nucleotide-resolution, genome-wide techniques to identify protein-RNA interactions (Konig et al., 2010; Nat Struct Mol Biol. 17(7): 909-15). We demonstrated how hnRNP C binds to enhanced and repressed splice sites. Recently, we discovered how competitive binding between U2AF65 and hnRNP C at protects the transcriptome from the detrimental exonisation of thousands of Alu elements (Zarnack et al., 2013; Cell. 152(3): 453-66). 

Figure 1

Figure 1. Schematic explaining how hnRNP C-binding to pre-mRNAs aids accurate splicing, whereas its loss leads to abberant exonisation. (Click to view larger image)

Statistical models of gene expression in fly development

Using compiled in situ hybridisation images from the Virtual Embryo dataset, we developed statistical models that for the first time accurately reproduce even skipped expression. Importantly, the models precisely forecast behaviours beyond the training data, making them truly predictive (e.g. effects of regulatory perturbations). The study generated experimentally testable hypotheses and provided new insights into the underlying mechanisms of transcriptional regulation (Ilsley et al., 2013; Elife. 2: e00522)

Figure 2

Figure 2. A. Predicted expression of even-skipped stripe 2 (eve 2) in wild type Drosophila embryos. B. Predicted eve 2 expression in giant (gt) mutant Drosophila embryos. C. in situ hybridisation image of gt mutant from Small et al., 1992: EMBO J. 11(11): 4047-57 (Click to view larger image)

Future work

Nuclear organisation of chromosomes

It is increasingly appreciated that the spatial organisation of chromosomes profoundly influences gene expression; however the details of how this is achieved are poorly understood. We will build on our successful collaborations with the Akhtar laboratory (Max Planck Institute of Immunobiology and Epigenetics, Freiburg) to study the effects of X-chromosomal positioning on dosage compensation. Excitingly, we recently initiated collaborations with Peter Fraser (Babraham Institute, Cambridge), a world-expert on ChIA-PET and Hi-C, to investigate nuclear organisation in mammalian cells.

Gene regulation in disease states

We will apply our basic knowledge of gene regulation to disease systems. There are indications that bacterial infections cause changes to the host's regulatory system, so affecting expression patterns. We have initiated collaborations with Richard Hayward (University College London) to apply genomic techniques to investigate the prevalence of these effects, and the influence they have on the progression of bacterial infections.

Gene regulation and DNA-damage repair

A major implication of our mutation rate study is that highly expressed genes are preferentially protected from DNA damage; however mechanisms such as transcription-coupled repair do not explain our observations. There are early indications that similar mechanisms operate in cancer. DNA damage repair is traditionally studied from a molecular perspective: we have initiated collaborations with the Mammalian Genetics Group to examine this phenomenon from a genomic viewpoint also. This will dramatically improve understanding of how DNA damage repair operates on a genome-wide scale.

Nicholas Luscombe

nicholas.luscombe@crick.ac.uk
+44 (0)20 379 61132

  • Qualifications and history
  • 2000 PhD from University College London, UK
  • 2004 Postdoctoral Fellow, Yale University, USA
  • 2005 Group Leader, EMBL-European Bioinformatics Institute, Cambridge, UK.
  • 2012 Established lab London Research Institute, Cancer Research UK, Professor of Computational Biology, University College London, UK
  • 2011 Adjunct Faculty, Okinawa Institute of Science & Technology, Japan
  • 2015 Winton Group Leader, the Francis Crick Institute, London, UK