Clinical Lecturer in Endocrinology

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

Obesity is a serious medical condition that causes diabetes, heart disease and cancer. There is a great need to identify new mechanisms of disease and targets for interventions to prevent or treat obesity.
Epigenetic switches on DNA turn nearby genes on and off without changing the underlying genetic code. These switches differentiate one cell from another in the same person, make genetically identical twins different, and are considered to be important causes of obesity and diabetes. The overall goal of our research is discover epigenetic switches and genes controlled by these switches that contribute to human obesity and diabetes.
Fat cells have very important roles in obesity and diabetes. These cells store and burn fat under different conditions. They also make hormones that control appetite and sugar levels in blood.
We have discovered multiple epigenetic switches in fat cells that are changed in obese people and genes that these switches are likely to control. We are currently exploring whether and how these switches alter gene activities, and what these genes do in fats cells to promote obesity or diabetes. To achieve this we are using human DNA sequencing and advanced technologies for manipulating switches and genes in fat cells and models of human obesity. We are also developing approaches to identify switches and genes in other cells involved in obesity and diabetes.
Ultimately, we hope to use these switches and genes as targets for new obesity and diabetes treatments.

Technical Summary

Obesity affects >600M people worldwide, accounts for ~60% of type 2 diabetes (T2D) and ~20% of cardiovascular disease, and causes >3M deaths each year. Better understanding of the molecular mechanisms underlying obesity and its metabolic complications is essential for development of much needed new therapeutics.
Epigenetic programming of gene expression and cell functions in response to genetic and environmental exposures is widely implicated in human obesity and metabolic disease pathogenesis. In exploratory human studies, epigenomic variations and their enzymatic regulators are widely associated with obesity phenotypes and major aetiological risk factors. However, examples of causal epigenomic variants in humans are very limited.
A major goal of our research is to identify human epigenomic variations and subsequent responses in gene expression that impact obesity phenotypes, then exploit their therapeutic potential. Our strategy is to use high-throughput genomics to discover cell-type specific epigenomic variations linked to human obesity, then state-of-the-art genome-editing tools to assign causation to these variants and their target genes. The discovery of causal human epigenomic changes is a prerequisite for leveraging the therapeutic potential of these reversible mechanisms of disease.
Adipose tissue cell-types are the primary focus of our research because of their key roles in obesity and metabolic disease pathogenesis – excess energy storage (white adipocytes), reduced inducible thermogenic energy expenditure (beige adipocytes), and adipo/cytokines effects on systemic energy balance, inflammation and insulin sensitivity (white and beige adipocytes in cross-talk with macrophages and other immune cells).
We have used integrated genomic strategies to discover alterations in adipocyte DNA methylation, an important epigenetic mechanism, robustly associated with human obesity and their predicted effector transcripts (cis- target genes). These loci may contribute to human obesity phenotypes if DNA methylation actively regulates the expression of cis- target genes with critical adipocyte functions. Our immediate aim is to establish the cause-and-effect relationships between DNA methylation, cis- target gene expression and disease phenotype, and the underlying mechanisms-of-action, at these loci. Our strategy is to combine complementary lines of evidence from human functional genomics (e.g. targeted bisulfite sequencing, Capture HiC, transcription factor motif analyses), in vitro epigenetic editing (CRISPR-cas9) and in vivo mouse genetic manipulation (Cre-Lox).
In parallel, we are developing single cell sequencing approaches to investigate epigenomic and transcriptomic mechanisms in other major adipose tissue cell types – macrophages, other immune and stromovascular cells, adipocyte precursors – underlying human obesity, metabolic dysfunction and weight loss.
By intersecting results from epigenomics, genetics, molecular signaling and physiology, our work will deliver new insights into mechanisms of disease in human adipocytes, and a range of translational research targets for obesity and T2D.

Publications

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