META-ANALYSIS OF GENE EXPRESSION HETEROGENEITY IN BRAIN DEVELOPMENT AND AGING

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2022-9-1

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Işıldak, Ulaş

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Aging is a complex process associated with the accumulation of stochastic genetic and epigenetic alterations, leading to functional decline and increased risk for disease and death. Although some previous studies demonstrated a tendency towards increased inter-individual heterogeneity during aging, whether it is a function of time that starts at the beginning of life is unknown. Its functional consequences and regulations have also not been systematically studied. In this study, I addressed these questions by the meta-analysis of 19 microarray age-series datasets, comprising 17 brain regions of 298 individuals. Investigating the age-related gene expression heterogeneity changes, I found that there is a significant shift towards increased heterogeneity consistency during aging (20 to 98 years of age) compared to the post-natal development period (0 to 20 years of age). Moreover, the genes that become more heterogeneous consistently across all aging datasets were found to be associated with biological processes and pathways that are related to neuronal function (i.e., axon guidance, postsynaptic specialization) and longevity (i.e., autophagy, mTOR signaling). Gene set enrichment analysis for transcriptional regulators (i.e., miRNAs and transcription factors) further revealed a positive correlation between the number of regulators and consistent changes in heterogeneity, indicating the possible role of transcriptional regulators in the underlying mechanism. Overall, the results presented here demonstrate that increased inter-individual expression heterogeneity is a general characteristic of the aging human brain, which is associated with multiple lifespans and disease-related pathways and processes, suggesting that increased heterogeneity may contribute to the emergence of aging-associated phenotypes.

Subject Keywords

aging, development, gene expression, heterogeneity, brain

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https://hdl.handle.net/11511/99569

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Graduate School of Natural and Applied Sciences, Thesis

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Citation Formats

U. Işıldak, “META-ANALYSIS OF GENE EXPRESSION HETEROGENEITY IN BRAIN DEVELOPMENT AND AGING,” M.S. - Master of Science, Middle East Technical University, 2022.