Project No. – 2019

Primary Supervisor

Professor Gareth Thomas – University of Southampton

Co-Supervisor

Dr Tim Fenton – University of Southampton

Summary

Background: Fibroblasts play a major role in maintaining tissue homeostasis; they are responsible for extracellular matrix production and remodelling, but also play an active role in regulating inflammation. Mis-regulated fibroblast activation leads to tissue fibrosis and inflammation, end-stage results of many degenerative pathologies associated with ageing.

A number of epigenetic regulatory mechanisms have been linked to the ageing process, including changes in DNA methylation, histone modifications and chromatin remodelling. Although it is estimated that >40% of all deaths are fibrosis-related in some form or other, little is known about the epigenetic changes that occur in fibroblasts from different tissues during ageing, or how this ultimately effects gene expression and cell function. We have recently uncovered significant differences in the DNA methylation landscapes of fibroblasts isolated from different tissues. We have also developed the methodology for single cell RNA sequencing (scRNASeq) of human tissues, and used this characterise fibroblast heterogeneity in normal human lung tissue and cancer, identifying seven fibroblast subpopulations that are differentially associated with clinical outcome.

Hypothesis: Fibroblasts from different tissues will show common age-related methylation and transcriptomic changes that alter cell function.

Aim: To perform methylation and scRNASeq profiling of human skin and upper aerodigestive tract mucosa from young (<20 years) and old (>60 years) patients to compare age-related changes in fibroblasts from these tissues.

Methods: This project will employ both wet-lab and computational methods, combining use of single-cell RNA-sequencing, DNA methylation and chromatin state analyses to profile the changes that occur in fibroblasts during the ageing process.

Deliverables: This study will provide the first epi-transcripomic analysis of fibroblasts from different tissues and identify age-related epigenetic and transcriptomic changes associated with altered cell function. The knowledge gained will enhance our fundamental understanding of tissue-specific fibroblast ageing and identify candidate biomarkers and targets for therapeutic modulation.