Regulation of Gene Expression

The ability to switch protein-coding genes ‘on’ and ‘off’ is a fundamental process shared by all cell types. In eukaryotic cells there is no such thing as ‘naked DNA’. All DNA is wrapped up into a protein straight-jacket, whose basic repeat, the ‘nucleosome’, must be countered in order to activate a gene. We study fundamental aspects of gene regulation, from transcriptional initiation to histone modification and chromatin remodelling. The 20,000 protein coding genes in the human cell produce a repertoire of ~100,000 proteins through the process of alternative splicing. Using a combination of in vitro, cellular and NMR techniques we also examine the basic mechanisms of splice site selection.

Research Groups

There are nine research groups working in the area of gene expression.  We utilize bacterial and human cells to produce recombinant proteins for biophysical and structural studies, using NMR, X-Ray crystallography and cryo-EM. To examine the role of histone modifying enzymes and transcription factors in vivo we use a combination of embryonic stem cells, primary cell lines (e.g. MEFs, B-cells, etc.) and genetically altered mice. Our work is supported by BBSRC, MRC and the Wellcome Trust.

Areas of focus

• Shaun Cowley - The physiological role of Histone Deacetylase (HDAC) complexes
• Cyril Dominguez - structure-function relationships of RNA binding proteins involved in alternative splicing
• Ian Eperon - Mechanisms of selection of splice sites in pre-mRNA
• Olga Makarova – Spliceosome assembly
• Daniel Panne - Structural biology of signal transduction and epigenetic gene regulation
• Thomas Schalch – Chromatin structure and function
• John Schwabe - Structural biology of transcriptional repression complexes

Our projects have helped to make significant contributions to the understanding of gene regulation at a molecular level. Through collaborations with clinical colleagues and researchers in Departments such as Chemistry and Physics, we address fundamental mechanisms underlying gene expression and apply this information in the design of novel therapeutics for the patient. Research of key histone modifying enzymes (e.g. EP300, HDAC1, etc.), to define their substrate specificity and complex components, will help guide their use as drug targets. Similarly, the application of oligo therapy for targeting and correcting aberrant alternative splicing in disease is proving to be a highly promising therapy. These strategies also contribute to the Leicester Institute of Structural and Chemical Biology (LISCB), co-housed within the Henry Wellcome building.

Achievement Highlights

• Zhang Y, Brown K, Yucong Yu, Ibrahim Z, Zandian M, Xuan H, Ingersoll S, Lee T, Ebmeier C, Zhang J, Panne D, Shi X, Ren X, Kutateladze T Nuclear condensates of p300 formed though the structured catalytic core can act as a storage pool of p300 with reduced HAT activity Nature Communications 12, 4618

• Godwin Job et al., PI: Thomas Schalch. 'SHREC Silences Heterochromatin via Distinct Remodeling and Deacetylation Modules' Molecular Cell volume 62:2 pages 207-221 (2016)
• Millard CJ, Fairall L, Ragan TJ, Savva CG and Schwabe JWR. The topology of chromatin-binding domains in the NuRD deacetylase complex. Nucleic Acids Research 48:22, 12972–12982
• Carika Weldon et al., PI’s: Ian Eperon & Cyril Dominguez. 'Identification of G-quadruplexes in long functional RNAs using 7-deazaguanine RNA'. Nature Chemical Biology volume 13, pages 18–20 (2017)