Transcriptome and molecular analyses reveal GREM1 as a potential regulator of cellular senescence .

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Bibliographic Details
Author / Creator:Baker, Samuel W.
Description:129 p.
Format: E-Resource Dissertations
Local Note:School code: 0330.
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Other authors / contributors:University of Chicago.
Notes:Advisor: Bruce Lahn.
Thesis (Ph.D.)--The University of Chicago, Division of the Biological Sciences and The Pritzker School of Medicine, Committee on Cancer Biology, 2015.
Dissertation Abstracts International, Volume: 76-08(E), Section: B.
Summary:The main goal of my thesis is to understand the mechanism(s) that regulate cellular senescence. In Chapter 2, I perform comparative analyses of gene expression data obtained from cells that underwent Telomere-Dependent Senescence (TDS), Telomere-Independent Senescence (TIS), and their replicating counterparts, Pre-TDS, Pre-TIS, and Bypass-TIS. I show that the largest gene expression difference across all comparisons is between replicating cells and senescent cells. I also show that gene expression profiles of TDS and TIS cells are distinct, such that transcriptome profiles of cells that underwent TDS look more similar to each other than that of cells that underwent TIS cells and vice versa. Additionally, I identify three genes (GREM1, PCDHGA10, and SLC9A3R1) with TIS-specific gene expression patterns. In Chapter 3, I focus on understanding the function and regulation of GREM1, a cancer-associated gene with a TIS-specific gene expression pattern. I show that the down-regulation of GREM1 in senescent cells occurs in a senescence-dependent, but time- and DNA-damage-independent manner. I demonstrate that over-expression of GREM1 increases both the rate of proliferation and replicative lifespan of normal human lung fibroblasts, supporting the known role of GREM1 in tumorigenesis. I also explore the regulation of GREM1 gene expression in the context of TIS. I show that the GREM1 promoter CpG island is significantly more methylated in TIS cells when compared to the other cell types used in our study including TDS, Pre-TDS, Pre-TIS, and Bypass-TIS. Lastly, I perform a cell fusion assay in which GREM1 gene expression is measured from both human and macaque genomes and demonstrate that GREM1 is expressed only from the macaque genome when TIS cells are fused with macaque cells, confirming that GREM1 is cis-silenced in TIS cells. In sum, the results I present here represent the culmination of a study to define the gene expression changes that occur in cells when they undergo TIS. Additionally, I demonstrate that GREM1 plays a role in regulating cell proliferation and replicative lifespan. Finally, the evidence presented here indicates that GREM1 is a potential regulator of TIS.