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You searched for +publisher:"University of Michigan" +contributor:("Cheung, Vivian"). Showing records 1 – 2 of 2 total matches.

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University of Michigan

1. Richards, Allison Leigh. RNA Editing at Baseline and Following Endoplasmic Reticulum Stress.

Degree: PhD, Human Genetics, 2015, University of Michigan

RNA sequences are expected to be identical to the DNA template. However, some RNA processing steps, such as RNA editing, can lead to differences in the RNA sequence that affect the fate of the RNA transcripts or the resultant proteins. My thesis focuses on the regulation of the canonical A-to-G editing and non-canonical RNA-DNA sequence Differences (RDD). My work contributed to the identification of RDDs throughout the human transcriptome. We identified all 12 types of single base differences across multiple individuals and various tissue types. We also detected peptides matching the RDD-encoded sequences suggesting that RDDs are translated into proteins. In subsequent work, we found that the non-canonical RDDs are found in nascent RNA. Through the use of nuclear run-on assays, we found that RDD occurs within seconds of exiting the RNA polymerase complex. Chapters 4 and 5 discuss my study of canonical A-to-G editing mediated by Adenosine Deaminase Acting on RNA (ADAR). First, we found that A-to-G editing levels differ across individuals. I searched for and identified genetic variants whose alleles are associated with editing levels of sites in the same gene. These data demonstrate that ADAR editing is cis regulated and can lead to individual variability in editing levels. Furthermore, by utilizing individual variability in editing and studying the relationship between editing sites, I learned how ADAR edits multiple sites in a given transcript. My data support a model where ADAR edits multiple sites along one side of a double-stranded RNA structure. To learn about the biological significance of RNA editing, I focused on endoplasmic reticulum (ER) stress. I found that editing levels change following ER stress suggesting that these RNA processing steps play a role in the ER stress response. Together, this work sheds light on the regulation of RNA editing and RDDs in the human transcriptome and aids in the understanding of how these processes may play a role in cellular response to stress. Advisors/Committee Members: Cheung, Vivian (committee member), Klionsky, Daniel J (committee member), Ginsburg, David (committee member), Ganesh, Santhi K (committee member).

Subjects/Keywords: RNA Editing; Genetics; Science

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Richards, A. L. (2015). RNA Editing at Baseline and Following Endoplasmic Reticulum Stress. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/116721

Chicago Manual of Style (16th Edition):

Richards, Allison Leigh. “RNA Editing at Baseline and Following Endoplasmic Reticulum Stress.” 2015. Doctoral Dissertation, University of Michigan. Accessed July 20, 2019. http://hdl.handle.net/2027.42/116721.

MLA Handbook (7th Edition):

Richards, Allison Leigh. “RNA Editing at Baseline and Following Endoplasmic Reticulum Stress.” 2015. Web. 20 Jul 2019.

Vancouver:

Richards AL. RNA Editing at Baseline and Following Endoplasmic Reticulum Stress. [Internet] [Doctoral dissertation]. University of Michigan; 2015. [cited 2019 Jul 20]. Available from: http://hdl.handle.net/2027.42/116721.

Council of Science Editors:

Richards AL. RNA Editing at Baseline and Following Endoplasmic Reticulum Stress. [Doctoral Dissertation]. University of Michigan; 2015. Available from: http://hdl.handle.net/2027.42/116721

2. Daigneault, Jillian. The Role of NELF in Mediating Human Gene Expression.

Degree: PhD, Cancer Biology, 2017, University of Michigan

Transcription is the synthesis of RNA from a DNA template. Transcription has been shown to occur in three main steps, initiation, elongation and termination. Additional regulatory steps include a rate limiting step between initiation and elongation of RNA polymerase II (RNA Pol II) termed promoter-proximal pausing of RNA polymerase. Dysregulation at any stage of this process can lead to cancer development. There has been extensive work focusing on how drastic alterations to the transcription process contributes to cancer development; however, there has been less focus on how the fine-tuning steps of transcription regulation contribute to cancer phenotypes. Specifically, my thesis focuses on understanding the contributions of NELF-mediated pausing to cancer development. To begin, I focused on primary cells in order to better understand the function of NELF-mediated pausing in a normal context. My work has identified a global profile of paused genes in human cells. Following the completion of this profile, I wanted to identify pathways that were enriched for paused genes. I found that paused genes are involved in cancer associated pathways such as EGFR and TGFb signaling as well as general transcription and gene expression. After identifying human genes with paused RNA polymerases, I focused on studying NELF. I found that almost all genes with NELF enrichment are paused. A majority of these genes also require NELF to maintain the pause. I then wanted to investigate the biological consequences of NELF-mediated pausing. I found that the expression of more than half of NELF-mediated paused genes are regulated by NELF. These genes include those involved in the cancer-associated pathways EGFR, TGFb and VEGF signaling. I showed that besides localizing to gene promoters, NELF also targets other genomic regions. I found that approximately half of these sites are in enhancers, specifically those enhancers that are actively transcribed. We showed that the abundance of these eRNAs is dependent on NELF. Finally, we found that loss of transcription of these eRNA result in changes in expression of nearby genes. Upon identifying NELF as a key regulator of gene expression in normal cells, I investigated how this process contributed to the gene expression changes found in cancer. To begin, I identified paused genes in HT29 colorectal cancer cells. I found that many of the same pathways show pausing in both normal cells and cancer cells. I also found that most genes utilize pausing to reduce their expression in cancer cells. These genes were enriched for cellular senescence, cellular stress response and WNT signaling. My work provides insight into the role of RNA Pol II pausing in cancer development. I have shown that cancer-associated pathways, such as EGFR, are regulated by RNA Pol II pausing. I have also generated global profiles of pausing in both normal and cancer cells. In comparing these two profiles, I have identified differences in the function of pausing between normal and cancer cells. One of the key differences I… Advisors/Committee Members: Cheung, Vivian (committee member), Sekiguchi, JoAnn M (committee member), Lawrence, Theodore S (committee member), Day, Mark L (committee member), Fearon, Eric R (committee member), Ferguson, David O (committee member).

Subjects/Keywords: RNA Pol II Pausing; NELF; Genetics; Health Sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Daigneault, J. (2017). The Role of NELF in Mediating Human Gene Expression. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/138582

Chicago Manual of Style (16th Edition):

Daigneault, Jillian. “The Role of NELF in Mediating Human Gene Expression.” 2017. Doctoral Dissertation, University of Michigan. Accessed July 20, 2019. http://hdl.handle.net/2027.42/138582.

MLA Handbook (7th Edition):

Daigneault, Jillian. “The Role of NELF in Mediating Human Gene Expression.” 2017. Web. 20 Jul 2019.

Vancouver:

Daigneault J. The Role of NELF in Mediating Human Gene Expression. [Internet] [Doctoral dissertation]. University of Michigan; 2017. [cited 2019 Jul 20]. Available from: http://hdl.handle.net/2027.42/138582.

Council of Science Editors:

Daigneault J. The Role of NELF in Mediating Human Gene Expression. [Doctoral Dissertation]. University of Michigan; 2017. Available from: http://hdl.handle.net/2027.42/138582

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