Functional Gene Control

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

All cells in the body share the same DNA, but they look and work differently. To achieve this, our DNA contains multitudes of special regions that do not code for proteins, but rather work as “molecular switches” responsible for switching the genes on and off depending on cell type and condition on the basis of the current cell state and signals transmitted into the cell nucleus from the cell’s microenvironment. Work over the last decade has made it possible to identify these elements on the DNA with high confidence, but how exactly these elements work together to regulate specific genes is not fully understood. We are interested in the “ground rules” underlying the function of DNA regulatory elements and how these rules work together in practice, particularly in biological processes that result in changes in the activity of multiple genes, such as during the differentiation of embryonic stem cells and activation of immune cells. We combine high-throughput laboratory investigations of the cells’ chromosomal structure and conformation (primarily in human cells) with advanced computational analyses to study these questions. Our goal is to understand how exactly cells make and enforce decisions to alter the activity of multiple genes, and how these processes are perturbed in diseases such as developmental disorders and cancer.

Technical Summary

We are interested in how genomic and epigenetic information is integrated with extrinsic signals to establish functional patterns of gene expression. Our emphasis is on biological phenomena involving concerted changes in phenotype, such as cell differentiation and activation, and on the role of DNA regulatory elements such as enhancers in these processes. We combine experimental approaches (including genome-wide assays of chromatin state, enhancer-promoter contacts and gene expression) with advanced statistical and machine learning techniques to study these questions, focusing on human cells and taking advantage of genetic and epigenetic variation as ‘natural perturbations’ in this system. Our research builds on the foundations of our previous work on promoter-enhancer relationships, organisation of DNA regulatory elements and population genomics. Our goal is to delineate the ‘ground rules’ of gene regulation and, on their basis, generate functional models of gene control networks underlying transcriptional decisions. Interrogation and validation of these models will pinpoint key individual players (genes, DNA regulatory elements, extrinsic signals) and their regulatory relationships, as well as shed light on how they are affected in disease.

Publications

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