The Heller Lab studies the gene regulatory mechanisms that underlie psychiatric disease. To approach this problem, we apply preclinical mouse paradigms of drug addiction and depression to define functionally relevant histone modifications and transcription factors. Because the syndromes of addiction and depression persist long after cessation of the insult, chromatin remodeling is an attractive mechanism for such long-lasting effects and presents an intriguing target for therapeutic intervention. We use high-throughput sequencing and bioinformatic approaches, including machine learning, to identify genes at which drug- or stress-regulation of the epigenome correlates with changes in gene expression. Using novel epigenetic editing tools, we then target individual modifications and examine their causal relevance to transcription and behavior. This ‘bottom-up’ approach allows direct elucidation of the causal relevance of epigenetic remodeling in the brain.