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SUMMARY:It is not all in your genes - epigenetic regulation of human lung 
 repair - Dr Renata Jurkowska\, Cardiff University
DTSTART:20250522T150000Z
DTEND:20250522T160000Z
UID:TALK232018@talks.cam.ac.uk
CONTACT:125275
DESCRIPTION:Chronic lung diseases are one of the great challenges of moder
 n medicine\, with 540 million patients waiting for curative treatments. Ch
 ronic obstructive pulmonary disease (COPD) is a life-limiting and currentl
 y incurable disease where patients experience a progressive decline in lun
 g function. Currently\, the molecular mechanisms driving disease onset are
  poorly understood\, and there are no effective treatments. Considering th
 e environmental cause of COPD (cigarette smoke) and disease phenotypes\, i
 ncluding defective cell renewal and differentiation\, we hypothesised that
  COPD would be driven by altered epigenetic signaling in lung cells.\n\nUs
 ing whole-genome bisulfite sequencing\, we generated the first genome-wide
  DNA methylation maps at single CpG resolution of purified parenchymal fib
 roblasts\, airway basal cells and alveolar progenitor cells (AT2) across C
 OPD stages. We demonstrate that the epigenetic landscape is severely chang
 ed in COPD\, with changes occurring predominantly in regulatory regions\, 
 including promoters and enhancers. RNA sequencing of matched samples showe
 d dysregulation of key disease-relevant pathways involved in proliferation
 \, cell differentiation\, inflammation\, extracellular matrix organisation
  and viral immunity. Excitingly\, we identify epigenetic changes and gene 
 subsets dysregulated already\n\nin mild COPD\, providing a unique insight 
 into the early disease. Integration of profiling data identified epigeneti
 cally regulated pathways and candidate drivers of COPD phenotypes. We unco
 vered a strong anti-correlation between gene expression and promoter methy
 lation\, suggesting that disease programs in these progenitors might be re
 gulated by DNA methylation. Interferon (INF) signalling was the top upregu
 lated pathway in AT2 cells with the strongest association with DNA methyla
 tion loss in the promoter of downstream genes. Using DNA methylation inhib
 itors and CRISPR-based epigenetic editing in lung cell lines we validated 
 the link between methylation loss and activation of the IFN-signalling pat
 hway.\n\nOur data demonstrate that epigenetic regulation in COPD is an exc
 iting research field that should be explored in-depth\, as it can provide 
 important insights into COPD-driving cell populations and associated mecha
 nisms.
LOCATION:Hodgkin Huxley Seminar Room\, Physiology building\, Downing Site 
 CB2 3EG
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