Cracking the epigenetic “fibroblast activation lock” in fibrotic scars and cancer

Dr Emanuel Rognoni (primary)
Centre for Endocrinology
William Harvey Research Institute, SMD
Dr Tanya Shaw (secondary)
Centre for Inflammation Biology & Cancer Immunology
King’s College London

Abstract

Fibroblasts, the major cell population in connective tissues, are best known for their role in depositing and maintaining extracellular matrix. In homeostasis most fibroblasts quiesce, but are rapidly “activated” during tissue repair. While this is usually transient, it becomes persistent/irreversible in fibrotic diseases and cancer. We will explore the transcriptional and epigenetic changes inhibiting resolution of pathological fibroblast behaviours. Using physiologically relevant 3D-cultures we will screen fibroblasts from normal and diseased skin for intrinsically maintained pro-fibrotic phenotypes and dissect the epigenetic and transcriptional regulators by combining ATAC-seq and RNA-seq. Identified candidates will be functionally validated and evaluated for therapeutic applications.


References

1. Shaw TJ, Rognoni E. Dissecting fibroblast heterogeneity in health and fibrotic disease Current Rheumatology Reports. 2020, DOI: 10.1007/s11926-020-00903-w

2. Rognoni E, Pisco AO, Hiratsuka T, Sipilä KH, Belmonte JM, Mobasseri SA, Philippeos C, Dilão R, Watt FM. Fibroblast state switching orchestrates dermal maturation and wound healing. Mol Syst Biol. 2018, 14(8), e8174.

3. Philippeos C, Telerman SB, Oulès B, et al. Spatial and Single-Cell Transcriptional Profiling Identifies Functionally Distinct Human Dermal Fibroblast Subpopulations. J Invest Dermatol. 2018;138(4):811‐825.

4. Barallobre-Barreiro J, Woods E, Bell RE, Easton JA, Hobbs C, Eager M, Baig F, Mackenzie Ross A, Mallipeddi R, Powell B et al. 2019. Cartilage-like composition of keloid scar extracellular matrix suggests fibroblast mis-differentiation in disease. Matrix Biol Plus, 4, 100016. https://doi.org/10.1016/j.mbplus.2019.100016

5. Shaw, TJ, Martin, P. 2016. Wound repair: a showcase for cell plasticity and migration. Curr Opin Cell BIol, 42, 29-37.


BBSRC Area
Molecules, cells and industrial biotechnology
Area of Biology
AgeingCell Biology
Techniques & Approaches
BioinformaticsGeneticsImage ProcessingMathematics / StatisticsMicroscopy / ElectrophysiologyMolecular Biology