Mathematical Modelling of Gene Regulation
Co-workers: Axel Nyström, Tom Brown, Alberto Merchante González
The regulation of gene expression is a fundamental process in any organism, underlying its response to the environment and playing a major role in the development of disease. Until recently, our understanding of these processes has been focussed on the direct action of transcription factors at gene promoters and the networks of transcription factors that form complex biological circuits. Over the years, however, evidence has emerged supporting a picture of greater complexity with fascinating novel mechanisms of gene regulation; in particular, those involving antisense transcription and chromatin modifications.
We use mathematical modelling to elucidate the mechanistic basis of these novel mechanisms of gene regulation. Mathematical models allow for the investigation of postulated 'microscopic' mechanisms, which are usually inaccessible to direct experimentation, by the identification of the corresponding 'macroscopic' behaviours, which generally are accessible.
We work closely with experimental groups in an ongoing cycle of discovery: models developed from existing data are used to make predictions to be tested by new experiments which are then used to refine the models.
In the model organism, Saccharomyces cerevisiae, recent genome-wide data sets have shown pervasive transcription, including many examples where this is in antisense orientation to an annotated gene. Intriguingly, the presence of antisense transcription is seen to correlate with altered patterns of chromatin modifications. One hypothesis is that this disruption is present to enhance the plasticity of genes by continually resetting the chromatin. The mechanisms behind the regulation of genes by antisense are currently poorly understood. The elucidation of the action of antisense transcription in gene regulation is one of the current main areas of focus for the group in collaboration with the group of Jane Mellor in the Department.
A more recent area of focus for the group is the control of gene expression cycling in the yeast metabolic cycle, also in collaboration with the group of Jane Mellor. In this cycle, a significant fraction of genes oscillate in sequence and we are currently trying to understand how histone modifications and non-coding RNA are involved in the regulation of this.
- Angel, A., Song, J., Dean, C. and Howard, M. A Polycomb-based switch underlying quantitative epigenetic memory, Nature, 476, 105-108 (2011)
- Angel, A., Song, J., Yang, H., Questa, J.I., Dean, C. and Howard, M. Vernalizing cold is registered digitally at FLC. PNAS, 112, 4146-4151 (2015)
- Song, J., Angel, A., Howard, M. and Dean, C. Vernalization - a cold-induced epigenetic switch, Journal of Cell Science, 125, 3723-3731 (2012)
- Saunders T. E., Pan, K. Z., Angel, A., Guan, Y., Shah, J. V., Howard, M. and Chang, F. Noise reduction in the intracellular Pom1p gradient by a dynamic clustering mechanism, Developmental Cell, 22, 558-572 (2012)
Figure 1. Epigenetic information (heritable information without change to the DNA sequence) can be carried by a mechanism that includes modifications to the tails of the histone proteins that help to structure and compact DNA in eukaryotes
Figure 2. smRNA-FISH images of the mRNA of two genes that are regulated by antisense transcription.
Figure 3. Histone modification correlations in the yeast metabolic cycle.
Graduate Student and Postdoctoral Positions: Enquiries with CV welcome