Date of Graduation

5-2016

Document Type

Dissertation (PhD)

Program Affiliation

Biomedical Sciences

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Hui-Kuan Lin

Committee Member

Min Gyu Lee

Committee Member

Jianping Jin

Committee Member

Randy Legerski

Committee Member

Gary Gallick

Abstract

Dynamic changes in histone acetylation by various physiological cues play important roles in gene transcription and cancer. However, the cellular signaling underlying this regulation is not well understood. Here, we show that, in a glucose dependent manner, E3 ubiquitin ligase NEDD4 ubiquitinates histone H3 on previously unstudied lysine (K) 23/36/37 residues, which specifically recruits histone acetyltransferase (HAT) GCN5 for subsequent H3 acetylation. Genome-wide analysis of chromatin immunoprecipitation followed by sequencing (ChIP-seq) data sets reveals that NEDD4 regulates glucose-induced H3K9 acetylation at transcription starting site (TSS) and enhancer regions. Integrative analysis of ChIP-seq and microarray data sets also reveals a consistent role of H3 ubiquitination in transcription activation and H3 K9 acetylation in response to glucose. Functionally, we showed that NEDD4-mediated H3 ubiquitination is critical for tumorigenesis and that IL1A, IL1B and GCLM are important target genes to elicit the function of glucose-induced H3 ubiquitination in tumor sphere formation. Together, our study provides a new model for glucose-induced transcriptome reprograming and epigenetic regulation in cancer through inducing NEDD4-dependent H3 ubiquitination.

Keywords

H3 ubiquitination, Nedd4 and cancer stem cells, H3 acetylation by glucose

Available for download on Tuesday, May 02, 2017

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