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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
Recommended Citation
Han, Xiaoqing, "Identification and Characterization of a Notch Transcriptional Repressor Complex" (2017). Open Access Dissertations. 1906.
https://scholarlyrepository.miami.edu/oa_dissertations/1906