Trim24-Regulated Estrogen Response Is Dependent On Specific Histone Modifications In Breast Cancer Cells

<p>In this dissertation, I discovered that function of TRIM24 as a co-activator</p> <p>of ERα-mediated transcriptional activation is dependent on specific histone</p> <p>modifications in tumorigenic human breast cancer-derived MCF7 cells. In the first</p> <p>part, I proved that TRIM24-PHD finger domain, which recognizes unmethylated</p> <p>histone H3 lysine K4 (H3K4me0), is critical for ERα-regulated transcription.</p> <p>Therefore, when LSD1-mediated demethylation of H3K4 is inhibited, activation of</p> <p>TRIM24-regulated ERα target genes is greatly impaired. Importantly, I</p> <p>demonstrated that TRIM24 and LSD1 are cyclically recruited to estrogen</p> <p>responsive elements (EREs) in a time-dependent manner upon estrogen</p> <p>induction, and depletion of their expression exert corresponding time-dependent</p> <p>effect on target gene activation. I also identified that phosphorylation of histone</p> <p>H3 threonine T6 disrupts TRIM24 from binding to the chromatin and from</p> <p>activating ERα-regulated targets. In the second part, I revealed that TRIM24</p> <p>depletion has additive effect to LSD1 inhibitor- and Tamoxifen-mediated</p> <p>reduction in survival and proliferation in breast cancer cells.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2012

Author dc:creator

• Yiu, Teresa T

Contributors dc:contributor

• Michelle Barton, Ph.D.
• Gary Gallick, Ph.D.
• Pierre McCrea, Ph.D.

• TRIM24
• LSD1
• H3K4 methylation
• epigenetics
• estrogen receptor
• transcription
• Biochemistry
• Cancer Biology
• Medicine and Health Sciences
• Molecular Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/313

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1347