The role and regulation of TCF21 in fibroblast differentiation

Nicholson, Megan 2026. The role and regulation of TCF21 in fibroblast differentiation. MPhil Thesis, Cardiff University. Item availability restricted.

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Abstract

Fibroblasts regulate tissue repair and fibrosis, but in chronic obstructive pulmonary disease (COPD) they become persistently activated, driving remodelling and loss of function. Epigenetic mechanisms are increasingly recognised as key regulators of fibroblast fate. This project investigated the transcription factor TCF21, a mesenchyme-specific regulator of fibroblast identity, and its regulation by DNA methylation, to clarify its role in lung fibroblast biology and COPD. We profiled methylation patterns of TCF21 in human lung fibroblasts (HLFs) and the epithelial line A549. HLFs showed relative hypomethylation at CpG islands (CpGi), consistent with active expression, while A549 cells were hypermethylated and silenced. These findings support an epigenetic mechanism of TCF21 control, with CpGi 3 highlighted as a regulatory hotspot linked to the long noncoding RNA (lncRNA) TARID. Transforming Growth Factor-β (TGF-β) induced ACTA2 and COL1A1 expression in HLFs, confirming myofibroblast activation. In the healthy donor HLF102, TGF-β consistently downregulated TCF21, fitting with its reported antifibrotic role in other organs. Methylation changes under acute stimulation were minimal, suggesting transcriptional rather than epigenetic regulation. Donor variation was more influential: healthy fibroblasts showed lower baseline methylation at the transcription start site (TSS) and higher TCF21 expression, while smoker fibroblasts showed the inverse. This suggests cigarette smoke imposes an epigenetic memory, silencing TCF21 and predisposing fibroblasts to persistent activation. To study TCF21 in tissue, a mouse precision-cut lung slice (PCLS) model was established. PCLS remained viable for at least one week and responded to TGF-β with increased αSMA and COL1A1 expression, validating the model as an ex vivo fibrosis assay. Unlike isolated fibroblasts, TCF21 expression remained relatively stable, suggesting transcriptional rather than epigenetic regulation. The observed responses may also depend on fibroblast content and donor variation, underscoring the need for further validation in COPD tissue. Together, these findings identify TCF21 as a fibroblast-specific, epigenetically regulated transcription factor suppressed under profibrotic conditions, linking environmental injury to persistent fibroblast activation and airway remodelling in COPD.

Item Type:	Thesis (MPhil)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	23 October 2026
Last Modified:	23 Oct 2026 13:20
URI:	https://orca.cardiff.ac.uk/id/eprint/190394

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