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

Author

Teresa T. Yiu, THe University of Texas Graduate School of Biomedical Sciences at HoustonFollow

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