Gene co-expression networks and their use in understanding of neural regulatory alterations during neurodegeneration

Yin, Wencheng (2019) Gene co-expression networks and their use in understanding of neural regulatory alterations during neurodegeneration. PhD thesis, University of Lincoln.

Gene co-expression networks and their use in understanding of neural regulatory alterations during neurodegeneration
Yin Wencheng Life Sciences August 2019.pdf - Whole Document

Item Type:Thesis (PhD)
Item Status:Live Archive


Gene co-expression analysis is a recently developed approach for the analysis of cellular functional organization. It involves the genome-wide profiling of patterns of coordinated gene expression as well as changes in these patterns and associated cell physiology correlates. Such changes have been shown to provide critical insights on a range of biological processes including disease mechanisms and progression. As the functional significance and mechanisms underlying gene co-expression patterns remain unclear, in this thesis, I investigate using a systems biology approach, how gene co-expression emerges in gene regulatory networks (GRNs) in the first place and specifically how co-expression changes relate to changes in coregulatory patterns. We find that while transcriptional regulators fail to display correlated activity with their direct targets; co-expression emerges as the result of genes being actively co-regulated at a given time. Next, I apply gene co-expression approaches to the analysis of Alzheimer’s disease (AD), a neurodegenerative condition, using longitudinal transcriptional profiling in an animal model of AD, the 3xTg-AD mouse model. Specifically, using gene co-expression approaches, we looked at the relationship between pathological betta amyloid (Aβ) deposition, a key factor in AD’s aetiology, and covariations in learning and memory performance in line with global gene expression changes. We found widespread changes at every stage, before, during and after the onset of functional decline and that a distinct subset of down-regulated differentially expressed genes are specifically associated with both decline in cognitive performance and Aβ deposition, thereby potentially identifying a transcriptional signature directly linking pathological Aβ with AD’related functional decline. Combining expression data form the AD mice model and sporadic human post-mortem brain tissues, we also investigate changes in expression patterns associated with mitochondrial dysfunction in AD and found that while the nuclear-encoded mitochondrial genes do not show pronounced changes in AD compared with the healthy individuals, the global coordinated expression of these genes is significantly reduced in AD compared to the healthy individuals. While significant reductions in coordinated expression of mitochondrial genes where observed before and after the onset of AD-related functional decline in the mouse model, only late changes in the correlated expression are significantly different than those observed background genes, suggesting that specific regulatory alterations of the mitochondrial gene network only take place at late stages after the onset of AD-associated symptoms. Taken together these findings illustrate the importance of understanding the complex patterns of coordinated gene activity ultimately responsible for bringing about the functional complexity underlying both health and
disease states in the nervous system.

Divisions:College of Science > School of Life Sciences
ID Code:47510
Deposited On:08 Dec 2021 14:11

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