Date of Graduation
12-2012
Document Type
Dissertation (PhD)
Program Affiliation
Genes and Development
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Michelle Barton, Ph.D.
Committee Member
Gary Gallick, Ph.D.
Committee Member
Pierre McCrea, Ph.D.
Committee Member
Xiaobing Shi, Ph.D.
Committee Member
Jessica Tyler, Ph.D.
Abstract
In this dissertation, I discovered that function of TRIM24 as a co-activator
of ERα-mediated transcriptional activation is dependent on specific histone
modifications in tumorigenic human breast cancer-derived MCF7 cells. In the first
part, I proved that TRIM24-PHD finger domain, which recognizes unmethylated
histone H3 lysine K4 (H3K4me0), is critical for ERα-regulated transcription.
Therefore, when LSD1-mediated demethylation of H3K4 is inhibited, activation of
TRIM24-regulated ERα target genes is greatly impaired. Importantly, I
demonstrated that TRIM24 and LSD1 are cyclically recruited to estrogen
responsive elements (EREs) in a time-dependent manner upon estrogen
induction, and depletion of their expression exert corresponding time-dependent
effect on target gene activation. I also identified that phosphorylation of histone
H3 threonine T6 disrupts TRIM24 from binding to the chromatin and from
activating ERα-regulated targets. In the second part, I revealed that TRIM24
depletion has additive effect to LSD1 inhibitor- and Tamoxifen-mediated
reduction in survival and proliferation in breast cancer cells.
Keywords
TRIM24, LSD1, H3K4 methylation, epigenetics, estrogen receptor, transcription
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