About the Project
A PhD studentship is available in the Computational Regulatory Genomics Group, headed by Dr Boris Lenhard.
Regulation of gene expression is central to every aspect of biology – from the subcellular level, via the regulation of the cell cycle, to the development of body plans and organ systems in multicellular organisms. Our group uses methods of computational biology to study gene regulation at the level of whole genomes, including the structure and function of gene promoters, proximal and distal regulatory elements, and the communication between them.
Our goal is to understand the molecular and mechanistic basis for different modes of gene regulation associated with control of the cell cycle; multicellular processes (primarily early embryonic development and the wiring of the central nervous system), and responses to external stimuli in terminally differentiated cells. Key regulatory decisions in multicellular development and differentiation are made at a specialised subset of loci that harbour genes whose protein products are themselves master regulators of development and differentiation. The systems they regulate include the transmission of regulatory information between neighbouring cells. A central distinguishing feature of regulation at these gene loci are arrays of highly conserved regulatory elements spanning megabase regions around their target genes, arrangements known as genomic regulatory blocks (GRB).
In this project the student will analyse the unifying features of long-range developmental regulation in some of the most complex processes that involve regulatory coordination across multiple cells: primarily neuronal differentiation and plasticity, and the establishment of neuronal connections. The research will involve the investigation of regulatory events and rules governing the activity of developmental transcription factor genes, as well as a growing number of tightly regulated genes involved in mediating axon guidance and other types of regulated cell adhesion. The results should enable us to understand how complex genomic regulatory inputs are transformed into three-dimensional developmental patterns. These regulatory mechanisms are central to the pathogenesis of a range of diseases that involve aberrant cell-cell communication, such as different types of cancer, neurodevelopmental and psychiatric disorders.
The group has a strong track record of developing computational approaches to extract regulatory patterns from large amounts of functional genomic data, including advanced visualization and whole-genome analysis of sequence motifs and epigenetic changes. We have access to world-class high-performance computing facilities. With our collaborators within MRC CSC and worldwide, including international consortia such as FANTOM and ZF-HEALTH, we are in a privileged position to have our computationally-derived hypotheses tested experimentally, and to benefit from early access to original experimental data.
References
Akalin, A., Fredman, D., Arner, E., Dong, X., Bryne, J. C., Suzuki, H., Daub, C. O., Hayashizaki, Y., and Lenhard, B. (2009). Transcriptional features of genomic regulatory blocks. Genome Biol 10, R38.
Becker, T. S., and Lenhard, B. (2007). The random versus fragile breakage models of chromosome evolution: a matter of resolution. Mol Genet Genomics 278, 487–491.
Dong, X., Navratilova, P., Fredman, D., Drivenes, O., Becker, T. S., and Lenhard, B. (2010). Exonic remnants of whole-genome duplication reveal cis-regulatory function of coding exons. Nucleic Acids Res 38, 1071–1085.
Engelen, E., Akinci, U., Bryne, J. C., Hou, J., Gontan, C., Moen, M., Szumska, D., Kockx, C., van Ijcken, W., Dekkers, D. H. W., et al. (2011). Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes. Nat Genet 43, 607–611.
Engstrom, P. G., Fredman, D., and Lenhard, B. (2008). Ancora: a web resource for exploring highly conserved noncoding elements and their association with developmental regulatory genes. Genome Biol 9, R34.
Engstrom, P. G., Ho Sui, S. J., Drivenes, O., Becker, T. S., and Lenhard, B. (2007). Genomic regulatory blocks underlie extensive microsynteny conservation in insects. Genome Res 17, 1898–1908.
Ragvin, A., Moro, E., Fredman, D., Navratilova, P., Drivenes, O., Engstrom, P. G., Alonso, M. E., La Calle-Mustienes, de, E., Gómez-Skarmeta, J. L., Tavares, M. J., et al. (2010). Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3. Proceedings of the National Academy of Sciences 107, 775–780.