Date of Award
2024
Document Type
Thesis
Degree Name
Master of Science (MS)
Department
Pharmacology
First Advisor
Gary Stein
Abstract
While the transformation of cancer cells through epigenetic modifications has been recognized for some time, recent advances in genome-wide genomic and epigenomic sequencing has revealed the extensive presence of mutations in epigenetic regulators and the comprehensive scope of epigenomic changes in cancer cells. It is now evident that genetic and epigenetic mechanisms are not mutually exclusive and work in tandem to facilitate the acquisition of the characteristic traits of cancer.Mitosis plays a pivotal role in transmitting lineage specific transcriptional control, imparting phenotypic memory and determination of cell fate. Nuclear organization and three-dimensional architecture of the genome is disrupted during mitosis, yet daughter cells preserve their gene expression patterns and phenotypic state. During mitosis most transcription factors dissociate from promoter sequences as well as from bulk chromatin. However, around 20% of transcription factors and chromatin binding proteins are retained at their specific target sites. Retention of the RUNX1 tumor suppressor with target gene loci on mitotic chromosomes during cell division, a process we designate “Mitotic gene bookmarking,” which epigenetically sustains competency for gene expression during cell division. In this study, we are investigating the role of RUNX1 in maintaining the epithelial phenotype and its loss in transformation to the mesenchymal phenotype using degron technology, targeting the RUNX1 factor for rapid degradation, to directly establish the requirement for this tumor suppressor to sustain gene expression that is obligatory for physiological control of normal and tumor phenotypes. By combing the expression profiles of mature RNA and nascent transcript analysis we were able to measure rapid changes in the core of RUNX1 regulatory network and obtain a list of differentially expressed genes. Furthermore, loss of RUNX1 results in the emergence of a heterogenous population of cells that are resistant to apoptosis and undergo a transition between cellular states exhibiting partial EMT and phenotypic plasticity.
Language
en
Number of Pages
75 p.
Recommended Citation
Chavarkar, Priyanka Gajanan, "Investigating The Effects Of Loss Of Runx1 And Its Role In Mitotic Gene Bookmarking And Breast Cancer" (2024). Graduate College Dissertations and Theses. 1797.
https://scholarworks.uvm.edu/graddis/1797