Chris Ponting: Computational and Disease Genomics
CEROX-miRNA control of mitochondrial OXPHOS activities in health and disease (Wellcome Trust Investigator Award)
Low mitochondrial enzymatic activity is a shared feature of many neurological disorders, such as Parkinson’s disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington’s disease and certain forms of brain cancer. We are exploring the role of long non-coding RNA and micro-RNA in mitochondrial enzymatic activity, focusing on a novel class of RNAs, termed competitive endogenous RNAs which affect oxidative phosphorylation. A diverse range of experimental and computational approaches are being used, as well as newly generated animal models. The ultimate goal is to ameliorate oxidative stress in iPS cell-derived lines from patients with a variety of neurodegenerative or neuropsychiatric diseases including Alzheimer's and Parkinson's.
The Homunculus in our Thymus: A Cellular Genomics Approach (a Wellcome Trust Strategic Award, held jointly with Georg Holländer)
In this project we are investigating the molecular mechanisms by which thymic epithelial cells (TEC) activate expression of transcriptionally repressed loci across virtually the complete set of protein-coding genes. They thereby educate the immune system as to molecular ‘self’, allowing the distinction of foreign molecules as ‘non-self’. Interestingly, TEC thus foretell the ubiquitous and tissue-specific self-antigens that mature T cells will encounter even many years after they exit from the thymus. These studies are relevant to better understand the fundamental function of the immune system and to identify causes of autoimmune diseases.
Tracing genotype-phenotype relationships in single cells of a ‘dial-up’ cancer model (MRC Core programme)
This project will establish the mutational lineage of a cancer genome not just from the time of tumourigenesis but also over its premalignant phase. The spatiotemporal or reproducible aspects of this project were not previously possible owing to the lack of high resolution single cell technologies and a fully reproducible model system. Advances in sequencing (and soon, targeted resequencing) of single cells’ gDNA, coupled to a ‘dial up’ cancer model in the mouse, together now make this approach feasible. The cellular consequences of mutation will be inferred from assaying both the polyadenylated RNA fraction and the chromatin accessibility in exactly those cells whose gDNA has been sequenced. This project takes advantage of existing collaborations with Thierry Voet (WT Sanger Institute) on single cell multi-omics technologies, and with Susan Farrington/Malcolm Dunlop.
Linking DNA variants to susceptibility of complex disease (MRC Core programme)
We seek to determine the causal contribution made by transcription factor binding variation to disease susceptibility. Its aims are: (i) to test whether such binding differences contribute to the susceptibility of any trait or disease, and, if so, then (ii) to determine whether variable binding predicts trait variation or disease case/control status. Both immunological (manifested in lymphoblastoid cells) and neurological (neural precursor cells) traits are being considered. This project adapts and takes advantage of genome-scale technological advances, specifically TWAS (transcriptome-wide association studies) approaches.
Predicting and determining domain functions in transcription (MRC Core programme)
Transcription initiation and elongation in mammals is a complex process involving dozens of molecules. Despite the importance of understanding this process it remains unclear what proteins are essential for specific molecular activities, and how these relate evolutionarily to proteins studied in model organisms. In this project we are using cutting-edge sequence comparison approaches to predict the functions and evolutionary heritage of domains within transcription-related molecules, focusing initially on one with likely nucleic acid-binding function. Subsequently, computationally-derived hypotheses are being addressed experimentally in order to determine molecular activities. Further information on this research, which is being led by Dr Luis Sanchez-Pulido, can be found here.
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