Date of Award

5-2019

Document Type

Open Access Thesis

Degree Name

Master of Science (MS)

Department

Biology

First Advisor

Todd Riley

Second Advisor

Jill Macoska

Third Advisor

Alexey Veraksa

Abstract

Unlike the genome, cell transcriptome is dynamic and specific for a given cell developmental stage. Transcriptomics study is crucial to understand the functional elements of the genome to divulge molecular constituents of cells. The recent development of high-throughput sequencing technologies has provided an unprecedented method to sequence RNA and it has been emerging as the preferred technology for both characterization and quantification of the cell transcripts. Using “Tailor_Pipeline” we have analyzed diet-induced mouse and stromal fibroblast RNA-Seq samples and deciphers the differentially expressed genes that were significantly up- and downregulated and associated with several metabolic immune responses that presumably associated with liver disease. Analyzing the diet-induced mice model allowed us to encapsulate the transcriptional differences between diet-induced mice that can aid in the understanding of NAFLD and consequent liver pathogenesis. Identification of genes downregulated in metabolic processes and upregulated in immune responses indicate that mice model exhibiting liver disease. Moreover, the finding of a premalignant signature suggests that NAFLD may begin to progress towards hepatocellular carcinoma much earlier than earlier consideration.

Tissue fibrosis arises due to overgrowth, scarring of various tissues and is attributed to deposition of the extracellular matrix including collagen, influenced by the actions of several pro-fibrotic proteins that can induce myofibroblast phenoconversion. Though recent transcriptomics analysis reveals the cellular identity, its ability to provide biologically meaningful insights in fibrosis is largely unexplored. To unravel the mechanisms at the genetic level, we have considered TGFβ/TGFβR and CXCL12/CXCR4 transcriptomes in human stromal fibroblasts. Transcriptome profiling technology revealed CXCL12/CXCR4 axis is responsible for the activation of COPII vesicle formation, ubiquitination, and Golgi/ER localization/targeting. Especially, identification of CUL3 and KLHL12 are responsible for the transportation of procollagen from ER to the Golgi. Interestingly, over-expression of CUL3 and KLHL12 are highly correlated with procollagen secretion by CXCL12-treated cells, but not in TGFβ-, treated cells. Moreover, this analysis showed how activation of the CXCL12/CXCR4 axis promotes procollagen I secretion that responsible for the deposition of ECM which is a characteristic of fibrosis.

Comments

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