Date of Award

2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cellular, Molecular and Biomedical Sciences

First Advisor

Frances E. Carr

Abstract

The overall incidence of thyroid cancer has more than tripled over the past several decades, as has aggressive disease and mortality. The direct relationship between thyroid disease, thyroid hormone levels, and development of thyroid cancer is incomplete. Recent meta-analyses have indicated a higher risk of thyroid cancer for patients with thyroid diseases that reflect an altered thyroid-pituitary signaling axis, which can have profound impacts on the physiology of the thyroid gland. These largely unanswered questions regarding altered thyroid hormone signaling and its consequences for thyroid tumor growth present a significant clinical challenge. This dilemma may come from a lack of understanding of the target genes and pathways regulated by the thyroid hormone receptor beta (TRβ), and how those pathways respond to the presence of the ligand, thyroid hormone. This dissertation addresses the fundamental link between the loss of thyroid hormone signaling mediated by TRβ and thyroid cancer.

Transcriptional regulation in response to thyroid hormone is a dynamic process that maintains cellular homeostasis and identity in all tissues. In the first part of this dissertation, I propose an updated model using an integrated genomics approach to profile and characterize the cistrome of TRβ, map changes in chromatin accessibility, and capture the transcriptomic changes in response to thyroid hormone in normal thyroid cells. I demonstrate that thyroid hormone promotes significant shifts in TRβ genomic occupancy, which are associated with differential chromatin accessibility, and differential recruitment of chromatin remodeling complexes. These results establish selective recruitment of different chromatin remodelers to TRβ binding sites, revealing novel functions in regulating chromatin accessibility and gene expression. In total, this data supports a multi-modal regulation model for TR interaction with chromatin with at least three distinct modes defined by their T3-dependent occupancy, changes in accessibility, and differential recruitment of chromatin remodelers.

Altered gene expression programming in cancer cells is often a consequence of a loss of function of cell-type specific transcriptional control mechanisms. Genetic mutations and epigenetic silencing of TRβ is characteristic of thyroid, breast, and other tumors, and the loss of expression can be a marker for dedifferentiation in thyroid cancers. TRβ is recognized as a tumor suppressor and a positive prognostic indicator for increased survival. In the second part of this dissertation, I demonstrate that TRβ regulates critical tumor growth suppression pathways in thyroid cancer cells. Induction of TRβ signaling in thyroid cancer cells results in transcriptional reprogramming, and in reduced aggressive cancer phenotypes. This analysis identified TRβ regulated pathways and selected nodes as potential therapeutic targets for the most aggressive endocrine cancer, anaplastic thyroid cancer.

This dissertation uncovers novel insights into thyroid hormone signaling and development of thyroid cancer, and bridges a significant gap in knowledge within the field. Taken together the studies presented there represent one of the most comprehensive profiles of TRβ regulated gene expression and chromatin remodeling in normal and malignant cells

Language

en

Number of Pages

264 p.

Download

Share

COinS