As part of the NIAAA-funded Center for Alcohol, Dr. Grayson is the Director of the Epigenetic Core. The Core prepares RNA, DNA and Chromatin from multiple brain regions (frontal cortex, hippocampus, amygdala and ventral tegmental area) of rats chronically treated with ethanol, chronically treated rats subjected to a 24 hour withdrawal period and non-treated control rats. Following isolation, the material is processed for library preparation and sent to our collaborators at the University of Illinois Urbana Champaign next-generation sequencing. Following bioinformatics processing, the data are then further analyzed for gene networks and hub genes in the various brain regions. The goal is to better understand how each brain region responds to chronic ethanol exposure and withdrawal from chronic ethanol.
DNA methylation is an important epigenetic mark that plays a prominent role in regulating gene expression during development of the brain. For the last twenty years, we have been investigating the role of DNA methylation in regulating candidate genes that are down-regulated in SZ. We have determined that DNA methyltransferases, DNMT1 and DNMT3a, are elevated in the post-mortem brains of schizophrenia subjects and that DNA methylation is increased at selected genes associated with GABAergic neuron function. We continue to investigate the role of DNA methylation and hydroxymethylation in promoters of genes that are aberrantly expressed in post-mortem prefrontal cortex of SZ subjects and non-psychiatric controls.
Progress in developing new, more effective, and less toxic drugs to treat the complex symptomatology of schizophrenia and bipolar disorder has been hampered by the lack of objective diagnostic tools to assess prodromes, progression severity, and therapeutic responses to drugs. Additional fundamental barriers to the identification of new drugs to effectively treat SZ and BP disorder include the incomplete understanding of the etiopathogenetic mechanisms underlying the symptomatology of these diseases. We are using a mouse model in which pregnant dams are subjected to prenatal restraint stress to elicit a prolonged stress response in the fetuses. We have found that the adult offspring of these stressed mice exhibit altered behavioral and molecular endophenotypes characterized by increased DNA methylation at selected target genes. We are currently testing new molecules for their ability to alter DNA methylation patterns in the frontal cortex of these mice to develop better pharmacotherapeutic drugs.
The role of methylcytosine (5mC) and hydroxymethylcytosine (5hmC) in the brain of ASD is largely underexplored. We have examined the epigenetic marks 5mC and 5hmC at selected promoters of several genes that are down-regulated in ASD prefrontal cortex and cerebellum. Interestingly, results from these two brain regions are quite similar with respect to the regulation of several genes expressed in GABAergic neurons. This regulation is different from the corresponding non-ASD controls used in the study. That is, there are altered levels of MECP2 binding to selected gene promoters and altered expression of key epigenetic regulators such as TET1.