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UBC Theses and Dissertations

The regulatory landscape of the glioma-associated transcription factor Capicua Firme, Juan Marlo R.

Abstract

The metazoan developmental gene capicua transcriptional repressor (CIC) encodes a transcription factor that transduces receptor tyrosine kinase signaling into gene expression changes. Aberrant CIC function is implicated in oligodendroglioma (ODG) development since one CIC allele is lost while the other is mutated in ~70% of ODGs. We therefore investigated how CIC can affect gene expression at a genome-wide level by inactivating CIC in HEK293a cells and subsequently measuring gene expression changes using microarrays. From this, gene expression changes spanning entire chromosomes were detected. Additionally, 24 candidate CIC-regulated genes were identified in HEK293a cells that also have evidence of CIC-dependent regulation in ODGs sequenced by The Cancer Genome Atlas (TCGA). Of these 24 genes, 5 genes (CNTFR, DUSP6, GPR3, SHC3, and SPRY4) with reported functions in mitogen-activated protein kinase (MAPK) signaling and central nervous system (CNS) development were further validated to undergo CIC-dependent regulation in HeLa cells. Finally, investigating how different CIC mutations affect gene expression revealed that different types of ODG-associated CIC mutations either abrogated or potentially preserved CIC’s transcriptionally repressive activity. These findings shed insight into possible roles for CIC in regulating gene expression at a chromosome-wide scale, MAPK signaling, CNS development, and ODG development.

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Attribution-NonCommercial-NoDerivs 2.5 Canada

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