Title: Computational and Functional Genomics of Transcription and Transcriptional Gene Regulation
Funder: Medical Research Council

Abstract: The central interests of the Computational Regulatory Genomics group are genomics and epigenomics of gene regulation in higher eukaryotes. We discovered several fundamental features of genes under developmental regulation and established the link between the type of core promoter and its responsiveness to long-range regulation, and developed a number of widely used computational methods and data resources for studying the regulatory content of genomes. Our current aim is to understand the molecular and mechanistic basis for different modes of gene regulation associated with the control of cell cycle, multicellular processes and regulation in terminally differentiated cells. In addition to our models of long-range regulation, the newly available epigenomic data contains crucial information for distinguishing these modes in development, differentiation and disease. Our core research program is to identify the features of genes under different modesand regimes of gene regulation. Different genes have regulatory territories that vastly differ in size, are often nested, and exhibit distinct patterns of epigenetic modifications, or succession of such patterns. By investigating genomic regulatory territories, we want to establish sequence features and epigenomic patterns and sequence features associated with different modes of gene regulation. We want to find out which properties of genes, are responsible for the correct sorting and assignment of inputs in complex, nonlinear gene loci. Among the most exciting hypotheses we are currently investigating are the fundamentally different modes of regulation of genes in dividing vs non-dividing, terminally differentiated cells, and time-sharing of core promoters. We plan to investigate how complex input from the cell environment is interpreted by megabase-sized cis-regulatory arrays of these genes to result in tightly coordinated development of complex multicellular structures. Our primary focus is biological insight. Nonetheless, we develop reusable methods for our analysis, to be shared by the community. This has proven to be a highly productive approach for subsequent analyses. In the forthcoming period our method development will focus on i) Transcription factor binding and transcription factor complexes: We are developing a computational toolbox for the analysis and visualisation of large sets of transcription factor binding sites and other regulatory elements and their integration with other types of genome-wide data; ii) Computational methodology for comparative epigenomics – The next several years will witness the rise of the need to analyse hundreds or thousands of epigenomes simultaneously - across tissues, time courses, epidemiological cohorts or different species. Computational capacity expertise and tools for the analysis of this scale are currently largely unavailable. Building on and inspired by methods for the segmentation of epigenomic regions, we plan to build methods for the characterisation of individual regulatory elements and their ensembles around genes under complex regulation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE