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The Role of 5-Hydroxymethylcytosine in Gene Dysregulation of Epileptogenic Tubers in Tuberous Sclerosis Complex Patients

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Technical Report,30 Sep 2014,29 Sep 2015

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Wayne State University Detroit United States

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Most tuberous sclerosis complex TSC patients suffer from epileptic seizures. For many patients anti-epileptic drugs do not control seizures. TSC seizures are associated with cortical malformations called tubers, but not all tubers cause seizures. It is unknown why some tubers cause seizures while others do not. We are investigating the hypothesis that 5-hydroxymethylcytosine 5hmC in DNA contributes to dysregulation of epilepsy risk genes in epileptogenic TSC tubers. We are using semiconductor sequencing to characterize 5hmC in DNA of epileptogenic and non-epileptogenic brain tubers that were surgically resected from TSC patients to treat intractable epilepsy. During the reporting period we successfully implemented a method for base-resolution sequencing of 5hmC. We have also devised a bioinformatics strategy to enable comparison of genome-wide 5hmC profiles and identify regions of altered 5hmC abundance. Our preliminary results reveal localized genomic regions that have different 5hmC patterns in epileptogenic tubers compared to non-epileptogenic tubers and normal tissue. We are currently identifying such regions that are also proximal to known epilepsy risk genes. We will then measure gene expression levels for these genes. The outcomes of this research are expected to expand our understanding of the molecular contributors to epilepsy in TSC and identify novel therapeutic targets.

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