Gene regulatory networks in pancreatic islets and insulinoma

Abstract

Insulinomas are extremely rare pancreatic neuroendocrine (PNET) tumours that develop from the β-cells of the pancreas.β-cells are the only cells capable of producing the hormine insulin, and play a major role in glucose homeostasis but have extremely low proliferative ability under normal physiological conditions. Insulinomas feature dysregulation of insulin secretion and aberrant proliferation. Insulinoma development has been associated with genetic and epigenetic alterations leading to loss of cell fate. We collected a large set of insulinoma and human islet samples, and utilised published data from other PNETs. ChIP-seq of H3K27ac, ATAC-seq and RNA-seq were performed to infer the regulatory landscape of insulinomas and control samples. In silico pipelines and analyses methods were developed in order to characterise the β-cell physiological and aberrant regulatory networks, across different layers of gene regulation. By comparing unaffacted pancreatic islets and insulinomas I have identified widespread changes in enhancer activity and gene expression. I have described the gene-regulatory landscape of insulinomas, identified putative drivers and mechanisms of tumour development, and built thefirst insulinoma-specific gene regulatory networks.