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Publication Date

2017-07-13

Availability

UM campus only

Embargo Period

2017-07-13

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2017-07-11

First Committee Member

Anthony J. Capobianco

Second Committee Member

David J. Robbins

Third Committee Member

Niramol Savaraj

Fourth Committee Member

Mary Lou King

Fifth Committee Member

Zafar Nawaz

Abstract

It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner. Furthermore, results indicate that Notch recruits Polycomb Repressor Complex 2 (PRC2) and Lysine Demethylase 1 (KDM1A/LSD1) to these promoters, which leads to changes in the epigenetic landscape and repression of transcription. The demethylase activity of LSD1 is a pre-requisite for Notch-mediated transcriptional repression. In addition, a stable Notch transcriptional repressor complex is identified containing LSD1, PRC2 and the Notch ternary complex. These findings demonstrate a novel function of Notch and provide further insight into the mechanisms of Notch-mediated tumorigenesis.

Keywords

Notch; PRC2; LSD1; Transcriptional Regulation

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