GSBS Dissertations and Theses

Approval Date

2-11-2016

Document Type

Doctoral Dissertation

Academic Program

Cell Biology

Department

Cell and Developmental Biology

First Thesis Advisor

Gary S. Stein, PhD

Second Thesis Advisor

Anthony N. Imbalzano, PhD

Keywords

Cell Differentiation, Bone Development, Breast Neoplasms, Chromatin, Core Binding Factor Alpha 1 Subunit, Transcription Factors

Subjects

Dissertations, UMMS; Cell Differentiation; Bone Development; Breast Neoplasms; Chromatin; Core Binding Factor Alpha 1 Subunit; Transcription Factors

Abstract

Higher-order genome organization is important for the regulation of gene expression by bringing different cis-regulatory elements and promoters in proximity. The establishment and maintenance of long-range chromatin interactions occur in response to cellular and environmental cues with the binding of transcription factors and chromatin modifiers. Understanding the organization of the nucleus in differentiation and cancer has been a long standing challenge and is still not well-understood. In this thesis, I explore the dynamic changes in the higher-order chromatin structure in bone differentiation and breast cancer. First, we show dynamic chromatin contact between a distal regulatory element and the promoter of Runx2 gene, which encodes the Runtrelated transcription factor 2 (RUNX2) that is essential for bone development. Next, via using a genome-wide approach, we show that breast cancer cells have altered long-range chromatin contacts among small, gene-rich chromosomes and at telomeres when compared with mammary epithelial cells. Furthermore, we assess the changes in nuclear structure and gene expression of breast cancer cells following Runt-related transcription factor 1 (RUNX1) deficiency, an event frequently observed in breast cancer. Finally, I present the role of the central ATPase subunit of the SWI/SNF complex, SMARCA4 (BRG1), in mediating nuclear structure and gene expression. Taken together, the research presented in this thesis reveals novel insight and paradigm for the dynamic changes in disease and differentiation, as well as uncovers previously unidentified roles for two chromatin regulatory proteins, RUNX1 and SMARCA4.

DOI

10.13028/M2T01Z

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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