Characterising genomic regulation in human pancreatic development

Abstract

Characterising genomic regulation in human pancreatic development

Submitted by Ailsa MacCalman To the University of Exeter as a thesis for the degree of Doctor of Philosophy in Medical Studies in October 2023

This thesis is available for Library use on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement.

I certify that all material in this thesis which is not my own work has been identified and that any material that has previously been submitted and approved for the award of a degree by this or any other University has been acknowledged.

Abstract

The pancreas serves two crucial roles in the human body i) the regulation of blood glucose levels (endocrine function) and ii) the secretion of digestive enzymes (exocrine function). Both endocrine and exocrine components originate from the same multipotent stem cells, implying a complex pattern of gene regulation during development. However, our understanding of the genomic processes governing pancreatic development is limited, largely relying on data from animal models and cellular models. My thesis aimed to comprehensively investigate cellular, epigenomic, and transcriptomic changes in the developing human pancreas using a unique cohort of pancreatic tissue samples from fetal and adult pancreas tissue donors. Firstly, immunohistochemical staining techniques were employed to identify variations in cell proportions during development. Secondly, epigenomic changes across the development of the pancreas were explored, focusing on DNA methylation trajectories, and identifying genetic variants influencing these DNA methylation patterns. Finally, targeted long-read RNA sequencing was used to characterise alternative splicing events throughout pancreas development, unveiling previously unannotated transcripts. The findings from this thesis highlight the dynamic nature of gene regulation in fetal pancreas as it develops in utero. This new knowledge enhances our understanding of cellular and genomic regulation during pancreatic development and provides valuable insights into the molecular mechanisms governing developmental programs. Ultimately, these insights may contribute to a better understanding of the origins of pancreatic diseases, opening doors for potential advancements in their prevention and treatment.