Role of DNA methylation in regulating striatal molecular rhythm alterations in depression

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PROJECT SUMMARY/ABSTRACT Major depressive disorder (MDD) is a leading global cause of disability. A prominent feature of MDD is circadian rhythm disturbances. Recent studies have shown gene expression (GE) rhythms in the human brain using a “time of death” analysis of postmortem (PM) brain tissue, where GE data is organized across a 24-hour clock based on individual time of death. Using this approach, it was previously shown that MDD subjects have disrupted GE rhythms across a number of brain regions, including the striatum. The striatum is composed of the dorsal striatum and ventral striatum and both have been implicated in stress, anhedonia, and depression. In preliminary studies, the candidate characterized GE rhythms and phase relationships across the human dorsal and ventral striatum. The mechanisms driving these rhythmic patterns of GE in the striatum and the alterations observed in MDD remain to be investigated. This K01 proposal utilizes a multi-omics approach to investigate DNA methylation (DNAm) as a potential epigenetic mechanism by which GE rhythms are altered in depression. Given that (1) DNAm in the striatum is strongly implicated in depression and directly influenced by stress and (2) DNAm rhythms are correlated and time-locked to GE rhythms in the human cortex, the central hypothesis is that striatal GE rhythm disruptions in depression are driven by chronic-stress induced alterations in DNAm rhythms. This hypothesis will be tested by the following aims: (1) Determine rhythmic changes in DNAm in the human PM dorsal and ventral striatum in MDD subjects; (2) Employ a multi-omics data integration approach to determine how rhythmic changes in DNAm affect transcriptome-wide rhythms in the human PM dorsal and ventral striatum in MDD subjects; and (3) Determine the regulation of transcriptome-wide rhythms and anhedonia-like behavior by DNAm in the dorsal and ventral striatum in a mouse model of chronic stress. These studies are central to understanding the mechanisms underlying circadian disruptions in MDD and may result in the discovery of novel therapeutic targets for future treatments. To complete the proposed studies and support his career goal of establishing an independent laboratory to study the epigenetic mechanisms driving circadian rhythm disruptions in depression, the candidate will require mentored training in: (1) developing conceptual and technical expertise in the use of rodent models and human PM brain tissue to study the neurobiology of depression; (2) developing conceptual and technical expertise in the field of epigenetics; and (3) learning advanced biostatistics and bioinformatics skills to integrate circadian analyses of transcriptomics and epigenomics data. To achieve these training goals, the candidate has assembled a mentorship team with extensive expertise in the neurobiology of depression, epigenetics, and biostatistics. The Department of Psychiatry at the University of Pittsburgh offers a well-funded environment with exceptional career development opportunities to become a successful independent investigator. At completion of this proposal, the candidate will be uniquely positioned to lead his own research program studying the epigenetic mechanisms driving circadian rhythm disruptions in depression.