Transcription start site usage in cancer heterogeneity

White, Paige-Louise (2024). Transcription start site usage in cancer heterogeneity. University of Birmingham. Ph.D.

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Abstract

Resolving intra tumour heterogeneity (ITH) remains an extensive therapeutic challenge in cancer research. Despite an emphasis on the importance of the transcriptional landscape in understanding cancer cell behaviours, the role of the core promoter remains widely ignored. Recent studies have shown the presence of alternative transcription start sites (TSS) and found a distinctive YC TSS enrichment in cancers that correlated with global phenotypes. However, tumour dynamics are underpinned by a complex network of sub clonal diversity therefore, the true biological significance of TSS usage remains elusive. Here we further characterise the phenotypic landscape of YC enriched cancers on both an inter and intra level. Through successful undertaking of single cell CAGE sequencing, we identify ITH of TSS usage even at a single cell level. We find differential YC enrichment associated with cellular physiological states that facilitate a growth phenotype. Next, we identify cell cycle phase associated TSS shifting and find YC enrichment associated with G0 and G1 phases. Scrutinisation of genes utilising YC enrichment showed subsets critically involved in directing the metabolic state of the cell. Overall, our findings highlight an important TSS association to cancer cell growth dynamics that act in a cell cycle dependent manner, even at a single cell resolution. Finally, attempts to characterise the spatiotemporal mapping of cycling phases through imaging emphasised the dynamic landscape of cancer behaviours. The work presented here further highlights the importance of TSS usage investigations that are masked in conventional gene expression analysis.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):