Molecular and epigenetic abnormalities in the subventricular zone stem cell niche in autism

Corley, Michael Jay
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[Honolulu] : [University of Hawaii at Manoa], [December 2013]
Autism is a prominent neurodevelopmental disorder associated with an array of neuropathological features including abnormalities in cellular growth, organization, and migration. However, an understanding of the underlying biological mechanisms involved in these neuropathological changes remains unknown. Insight into the neuropathology and etiology of autism may be gained by better understanding dysregulated developmental mechanisms in the autistic brain. In the brain, the subventricular zone (SVZ) is a region critical to regulating neurodevelopmental processes; yet, the role of SVZ region in autism has not been studied. Hence, this dissertation's goal was to identify molecular and epigenetic aberrations in the SVZ region of the brain at different stages of development to gain insight into biological mechanisms underlying abnormal brain development in autism. We aimed to complete this goal through histological analyses, next-generation sequencing gene expression profiling, and DNA methylation profiling of postmortem human brain tissue from autism-diagnosed and typically developing (TD) cases. In Chapter II, we located the SVZ region of interest in frozen tissue blocks and found the molecular constituents of the SVZ region, which are critical to regulating cellular proliferation, were deficient in young autism compared to TD samples suggesting abnormal control of neural growth in the SVZ region. Next, in Chapter III, we isolated high quality RNA from these and additional samples for next-generation sequencing in a genome-wide expression profiling study. Results identified distinct profiles of differentially expressed genes for autistic cases as a function of age. Most notably, genes regulating cell proliferation, differentiation, and migration were dysregulated in young autistic compared to TD cases. In Chapter IV, DNA was isolated from young autistic and TD cases and results identified different DNA methylation profiles in autistic cases for genes related to cell migration and brain development, suggesting an abnormal epigenetic regulation of key neurodevelopmental genes in the autistic brain. Altogether, this dissertation provides evidence for a dysregulation of molecular and epigenetic mechanisms in the SVZ region of the autistic brain. These novel findings may underlie the neuropathological features of autism across development, possibly contribute to the core behavioral aberrations of autism, and provide insight into uncovering the pathogenesis of autism.
Ph.D. University of Hawaii at Manoa 2013.
Includes bibliographical references.
autism, subventricular zone, postmortem brain, gene expression, epigenetics, DNA methylation
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