Regulatory Genomics and Metabolic Disease
Inês Cebola (Group Lead)
ICTEM Building, 5th floor
Du Cane Road
What we do
Most of the genetic factors that associate with common human diseases reside in noncoding sequences. We aim to understand how specific noncoding sequences can affect the regulation of metabolic functions and contribute to human metabolic disease. We apply both computational and experimental approaches to better elucidate molecular processes involved in the development of metabolic dysfunction, having a particular interest in non-alcoholic fatty liver disease and other pathologies affecting the liver. We also explore the intricate relationship between liver cell dysfunction and the development of type 2 diabetes and cardiovascular disease.
Why it is important
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease, affecting 25% of the world’s adult population. NAFLD associates with multiple clinical states, including obesity, insulin resistance, and type 2 diabetes, which affects over 400 million people worldwide. Despite the large incidence of NAFLD and T2D, there are still no personalised therapies targeting the molecular origins of these conditions. Therefore, there is a strong need to improve our understanding of the mechanisms by which different factors, including genetics, influence disease risk.
How it can benefit patients
Our research aims to pinpoint specific processes that are altered in individuals at high disease genetic risk, as well as in patients. Understanding of the molecular mechanisms by which genetic risk leads to changes in cell function will provide the basis for the future design of targeted therapies and preventive strategies.
Summary of current research
The purpose of our research is to better understand the molecular mechanisms of liver insulin resistance through the use of transcriptomic, genomic and epigenomic studies using liver cell line models and primary cultures. We are deploying liver “steatosis in the petri dish” models and CRISPR-Cas9 editing to address our research questions. Our current activities include:
- Characterisation of the epigenomic landscape of human liver cells in steady-state and pathophysiological conditions deploying human hepatocyte 3D cultures coupled with transcriptomic and epigenomic profiling.
- Development of CRISPR/Cas9 functional screens to identify noncoding sequences that directly impact liver cell metabolic outputs.
- Experimental validation of specific liver disease GWAS hits.
- Prof Mark Thursz
- Prof Guy Rutter
- Prof Anna Randi (National Heart & Lung Institute)
- Prof Jorge Ferrer
- Dr Christopher Rhodes (National Heart & Lung Institute)
- Dr Aida Martinez-Sanchez
- Dr Santiago Vernia (LMS-MRC)
- Dr Santosh Atanur
- Dr Toby Andrew
- Dr Beata Wojciak-Stothard
- Dr Michela Noseda
- Prof Inga Prokopenko (University of Surrey)
- Prof Catherine Williamson (Kings College London)
- Prof Seung Kim (Stanford University)
Accelerating Medicines Partnership (AMP) for Common Metabolic Diseases
- Beucher, A, Cebola, I. "One-step dual CRISPR/Cas9 guide RNA cloning protocol” Nature Protocol Exchange (2019) DOI:10.21203/rs.2.1831
- Miguel-Escalada, I.*, Bonas-Guarch, S.*, Cebola, I.* et al. Human pancreatic islet 3D chromatin architecture provides insights into the genetics of type 2 diabetes. Nature Genetics (in press). *co-first author
- Cebola, I. & Pasquali, L. Non-coding genome functions in diabetes. Journal of Molecular Endocrinology 56, R1–R20 (2016)
- Cebola, I. et al. TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors. Nature Cell Biology 17, 615–626 (2015)
- Weedon, M. N.*, Cebola, I.*, Flanagan, S. E.* et al. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nature Genetics 46, 61–64 (2014). *co-first author
- Epigenetics of Hepatic Insulin Resistance. H Maude, C Sanchez-Cabanillas, I Cebola. Frontiers in Endocrinology 12, 504 (2021)
- Liver gene regulatory networks: Contributing factors to nonalcoholic fatty liver disease. I Cebola. Wiley Interdisciplinary Reviews: Systems Biology and Medicine 12 (3), e1480 (2020)
Positions will be available soon.
Dr. Inês Cebola
Dr. Inês Cebola
Dr Hannah Maude
Dr Hannah Maude