Major depressive disorder (MDD) is a devastating mental illness arising from a combination of genetic, epigenetic, and environmental influences. Despite decades of investigation, our ability to diagnose and treat MDD remains limited, and a large fraction of MDD patients fail to respond to available treatment options. Epigenetic genome changes likely play a significant role in the pathophysiology of depression, especially since environmental stimuli and experience are important contributors to the development of MDD. We propose to couple technology development and circuit-specific epigenetic analysis of genome methylation and chromatin remodeling to reverse engineer the epigenetic mechanisms underlying major depressive disorder, and to discover novel drug targets for developing fundamentally new classes of antidepressants. Using animal models of depression we will identify specific circuits of cells in the brain whose functions are compromised in the disease state and determine the contributing epigenetic mechanisms. To enable the proposed research, we will develop an innovative platform of technologies to enable targeted genome and epigenome modifications and apply it to systematically identify epigenetic mechanisms in specific circuit components underlying depression. We will also explore the identified epigenetic mechanisms for developing new classes of antidepressants. In addition to our core technologies for genome and epigenome engineering, we will integrate a comprehensive range of technical expertise spanning electrophysiology, imaging, behavioral analysis, computational biology, synthetic biology, high-throughput genome and epigenome analysis, and highthroughput drug screening and assay development. The successful completion of our vision will yield four broad impacts: I. Pioneer a new approach for drug target discovery that has implications for a broad range of developmental and chronic illnesses. II. Develop a robust technology platform for large-scale targeted genomic engineering to enable more complete recapitulation of human disease genotypes in animal models. We will enable precise introduction of combinations of disease-associated genetic mutations into a single animal model. III. Develop a technology for targeted epigenome modification to enable direct functional testing of causal links between specific epigenetic modifications and disease pathophysiology. IV. Identify fundamentally new classes of therapeutics for major depression.

Public Health Relevance

Major depressive disorder is a devastating mental illness affecting millions of Americans annually, with a large fraction of patients unresponsive to available therapies. The proposed project aims to identify fundamentally new classes of therapeutics by probing the epigenetic mechanisms contributing to major depression, through a combination of innovative technology development, and systematically establishing causal links between epigenetic targets and disease phenotype. The technologies developed through this proposal will establish a new epigenetic paradigm for drug discovery and have broad impacts for many fields of biomedical research including cancer, diabetes, obesity, and other neurological disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZGM1-NDPA-A (01))
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Beckel-Mitchener, Andrea C
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Broad Institute, Inc.
United States
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Nishimasu, Hiroshi; Shi, Xi; Ishiguro, Soh et al. (2018) Engineered CRISPR-Cas9 nuclease with expanded targeting space. Science 361:1259-1262
Gootenberg, Jonathan S; Abudayyeh, Omar O; Lee, Jeong Wook et al. (2017) Nucleic acid detection with CRISPR-Cas13a/C2c2. Science 356:438-442
Smargon, Aaron A; Cox, David B T; Pyzocha, Neena K et al. (2017) Cas13b Is a Type VI-B CRISPR-Associated RNA-Guided RNase Differentially Regulated by Accessory Proteins Csx27 and Csx28. Mol Cell 65:618-630.e7
Yan, Winston X; Mirzazadeh, Reza; Garnerone, Silvano et al. (2017) BLISS is a versatile and quantitative method for genome-wide profiling of DNA double-strand breaks. Nat Commun 8:15058
Nishimasu, Hiroshi; Yamano, Takashi; Gao, Linyi et al. (2017) Structural Basis for the Altered PAM Recognition by Engineered CRISPR-Cpf1. Mol Cell 67:139-147.e2
Shmakov, Sergey; Smargon, Aaron; Scott, David et al. (2017) Diversity and evolution of class 2 CRISPR-Cas systems. Nat Rev Microbiol 15:169-182
Gao, Linyi; Cox, David B T; Yan, Winston X et al. (2017) Engineered Cpf1 variants with altered PAM specificities. Nat Biotechnol 35:789-792
Platt, Randall J; Zhou, Yang; Slaymaker, Ian M et al. (2017) Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits. Cell Rep 19:335-350
Joung, Julia; Konermann, Silvana; Gootenberg, Jonathan S et al. (2017) Genome-scale CRISPR-Cas9 knockout and transcriptional activation screening. Nat Protoc 12:828-863
Scott, David A; Zhang, Feng (2017) Implications of human genetic variation in CRISPR-based therapeutic genome editing. Nat Med 23:1095-1101

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