Mechanisms and Principles of Regulation of Gene Expression

Members of this MCB subtheme focus on the mechanisms by which gene expression is achieved and regulated ­ the central dogma of molecular biology ­ from the perspective of both basic mechanisms and disease related processes.  Their research spans the entire breadth of gene expression from epigenetic and molecular mechanisms to cell type-specific and developmental controls.

The fourteen research groups have particular expertise in the initiation and maintenance of transcriptional programs (Carr, Cowley, Drea, Luthi-Carter, Malewicz, Rosato, Schwabe, Twell), the control of pre-mRNA splicing (Dominguez, Eperon, Makarova) and the regulation of translation via miRNAs (Barlev, Bushell, Willis). Their research embraces methodologies ranging from the biophysical (X-ray crystallography, NMR), single molecule techniques, high-throughput genomics, to transgenic plants and animals.

In addition to the core groups there are associated groups and important collaborations in bioinformatics (e.g. Schmid, Blades) and with researchers investigating Genome Function within the Genome Science theme (eg. Heslop-Harrison, Higgins, Mallon, Pritchard, Pringle, Moody, Schwarzacher, Tanaka and Taylor).

The sub-theme members are keen to use the insights resulting from fundamental studies to develop new therapies and applications. For example, Prof. Ian Eperon and colleagues invented a method known as TOES (targeted oligonucleotide enhancers of splicing) to stimulate splicing of SMN2 exon 7. This is an important goal, because it would compensate for the loss of the SMN1 gene in patients with spinal muscular atrophy.

This combination of expertise has resulted in a number of major achievements:

The discovery of inositol tetraphosphate as a component of HDAC-containing co-repressor complexes, a paradigm shift in understanding how signaling is integrated into epigenetic gene regulation (Watson et al., 2012 Nature; Millard et al. Molecular Cell 2013).

The first use of single molecule methods to analyse the stoichiometry of regulatory proteins in RNA splicing and the use of novel chemical biology tools to show that interactions between distant sites on the RNA did not involve looping (Cherny et al. EMBO J. 2010).

That microRNAs inhibit gene expression by first inhibiting translation followed by mRNA degradation. The translation repression activity of microRNAs functions by affecting the mRNA unwinding activity of the eIF4F complex. (Meijer et al., Science 2013).

The identification of DUO1 as a ‘master’ regulator of gene expression programs that direct male germline development and differentiation in plants (Brownfield et al. PLOS Genetics 2009; Borg et al., Plant Cell 2011).

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College of Life Sciences
University of Leicester
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