The human forebrain plays critical roles in cognition, motor function, and emotion. Impaired forebrain development and function are associated with neurodevelopmental disorders, including epilepsy.
Early onset of epilepsy is a spectrum of disorders with strong genetic components that could be difficult to precisely diagnose and provide effective treatments. A major and underexplored cause of complex disorders could be mutations in gene regulatory elements. For example, disruption of these elements and subsequently the gene regulatory networks that are involved in brain development can lead to epilepsy subtypes such as infantile spasms (IS). However, the regulatory elements of forebrain expressed genes involved in IS are unknown. Using ChIP-Seq with enhancers and repressors marks, I will identify regulatory elements in the mouse embryonic day 16.5 (E16.5) developing forebrain. In order to determine which genes physically interact with these potential regulatory elements, I will carry out chromatin interaction analysis followed by paired-end tag sequencing (ChIA-PET) on E16.5 mouse forebrains. The interacted elements that are associated with IS genes will be tested for forebrain activity using zebrafish and mouse transgenic assays. Furthermore, the activity of positive enhancer sequences will be dissected using massively parallel reporter assays in a single nucleotide resolution to discover essential transcription factors required for forebrain activity. Altogether, these results will unravel a gene regulatory network of the developing forebrain, highlight functional IS-associated enhancers and determine the effect of mutations on their activity. This study will provide novel functional noncoding DNA sequences that play a role in epilepsy and other neurodevelopmental disorders.
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