UC San Diego

ABSTRACT OF THE THESIS

Myt1l Contributes to Reprogramming of Mature Hepatocytes to a Beta-cell Like State

by

Melissa Tran

Master of Science in Biology

University of California San Diego, 2020

Professor Marc Montminy, Chair

Professor Gen-Sheng Feng, Co-Chair

The goal of regenerative medicine is to replenish damaged and diseased cells in the body. In order to do so, mature cells are encouraged to convert towards another cell type. One way of doing this is by overexpressing specific genes using viral vector delivery. Previous research has shown that the beta cell specific transcription factors Pdx-1, NeuroD1, MafA, Insm1, Isl1, and Pax6 are able to shift liver cells and exocrine pancreas cells towards a beta cell-like state. In this experiment, we analyze different combinations of these lineage determining transcription factors and their reprogramming effects on mature hepatocytes. We were also prompted to investigate Myt1l, a gene that has previously only been found in neuronal tissue. Previous work done in the lab, however, has shown it to be highly enriched in islets, which may suggest that the gene plays a critical role in beta cell function. Here we show that combining the transcription factors Pdx-1, NeuroD1, MafA, Insm1, Isl1, Pax6 and Myt1l leads to a substantial shift towards a beta cell-like state based on the increased expression of IAPP, a beta cell marker that is co-expressed with insulin to regulate blood glucose levels with satiety signals. Furthermore, our results suggest that Myt1l is an important factor converting mature hepatocytes towards a more beta cell-like state. Based on transcriptomic characterization, experimental conditions in the presence of Myt11 when compared to the experimental conditions without Myt1l display an upregulation of beta cell markers that are closely related to insulin secretion. These observations provide evidence that Myt1l is a key beta cell reprogramming factor.