Evolution and Function of the Genomic Landscape in the Human Brain

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2019-01-22

Authors

Fontenot, Miles Ray

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Abstract

The molecular mechanisms underlying human brain evolution are not fully understood; however, previous work suggested that expression of the transcription factor CLOCK in the human cortex might be relevant to evolution of the human brain and human cognition and disease. In this dissertation, we investigated this novel transcriptional role for CLOCK in human neurons by performing chromatin-immunoprecipitation sequencing for endogenous CLOCK in adult neocortex and RNA-sequencing following CLOCK knockdown in differentiated human neurons in vitro. These data suggested that CLOCK regulates expression of genes involved in neuronal migration, and a functional assay showed that CLOCK knockdown increased neuronal migratory distance. Furthermore, dysregulation of CLOCK disrupts co-expressed networks of genes implicated in neuropsychiatric disorders, and the expression of these networks are driven by hub genes with human-specific patterns of expression. Thus, these data support a role for CLOCK-regulated transcriptional cascades involved in human brain evolution and function. We further created a humanized mouse model with increased neocortical expression of CLOCK to mimic the human pattern of expression, providing a novel system for in vivo mechanistic studies of CLOCK function. Finally, we have conducted preliminary gene expression analysis of the human epileptic brain compared to control tissue from donors without neuropsychiatric disease. These data will be correlated with in-patient recordings of neuronal activity to identify potential new avenues for investigation into epilepsy. In total, we have contributed a rich dataset of genomics dataset related to CLOCK function in human neurons, generated a novel humanized mouse model, and initiated an exciting study into the gene expression and function of the epileptic brain.

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