PROJECT SUMMARY – OVERALL The objective of this Conte Center is to take maximal advantage of recent advances in chromatin biology, so- called epigenetics, to fundamentally increase our understanding of the long-lasting abnormalities in the brain that cause depression. Our work focuses on key limbic brain regions, such as nucleus accumbens and prefrontal cortex, which have been implicated directly in the control of mood in health and disease. The Center is composed of four Projects led by Eric Nestler (Mount Sinai), Schahram Akbarian (Mount Sinai), David Allis (Rockefeller), and Carol Tamminga (UT Southwestern), and two Scientific Cores—the Animal Models Core led by Venetia Zachariou (Mount Sinai) and Chromatin and Gene Analysis Core led by Li Shen (Mount Sinai). The PIs, along with several Co-PIs, are leaders in their fields who use their complementary expertise and approaches to execute a multidisciplinary program of research focused on transcriptional and chromatin abnormalities both in mouse models of depression and in postmortem brains of depressed humans. A defining feature of the Center is bidirectional translation, with findings from mice validated in humans, and with discoveries in humans put back into animal models to study underlying mechanisms. The Center's research is defined by four themes. First, we study a broad range of epigenetic mechanisms, including histone and DNA modifications, nucleosome turnover, and the 3D structure of chromatin, which work in concert to control gene transcription. This involves the use of several next generation sequencing methods and advanced bioinformatics to analyze the resulting complex datasets. Second, we use this insight to understand how exposure to stress early in life controls an individual's susceptibility vs. resilience to stress-related disorders for a lifetime through long-lasting epigenetic mechanisms. Third, we focus on sex differences in this epigenetic regulation, having defined shared as well as many distinct mechanisms operating in male vs. female brain. Fourth, these studies are identifying numerous key target genes and molecular pathways that are defining novel mechanisms underlying depression and other stress-related disorders, which will help drive the field toward improved treatments and diagnostic tests.