Epidemiological studies provide mounting evidence supporting that environmental and experiential influences, such as stressful life events, interact with genetic variations and compound the risks for neuropsychiatric disorders, such as major depressive disorder (MDD). MDD afflicts about 6.7% of the United States adults, but treatment options for MDD are limited and not effective. The objective of this proposal is to define the global epigenetic landscape associated with stress experience and assess the effect of locus-specific epigenetic changes on the manifestation of depression-like phenotypes. We propose to first expose both male and female mice to chronic unpredictable stress paradigms. We will then take a genomic approach to identify the stress responsive epigenetic code in targeted neuronal cell types in the brain. Finally, we will modify and apply CRISPR/Cas9 technology to address the causal relationship between the identified epigenetic code to the expression of depression-like behaviors. With currently available state-of-the-art technologies and our newly developed, genetically modified mouse tools, we hope to gain an insight into the epigenetic mechanisms through which stress interacts with susceptibility genes and confers increased risk to MDD. Our proposed study will also allow greater understanding of the underlying causes of stress-related neuropsychiatric disorders and provide the necessary foundation for improved diagnosis and intervention.

Public Health Relevance

According to a recent estimate by the National Institute of Mental Health, each year about 6.7% of adults in the U.S experience major depressive disorder (MDD), but current treatment options are limited with low efficacy. Given that epidemiology studies have pointed to the influence of adverse life events and stressful experiences in the etiology of MDD, we aim to address the molecular mechanisms by which stress experience induces long-lasting changes in the epigenome, thus leading to sustained alteration in gene expression that underlie the etiology of MDD. An improved understanding of the molecular basis of stress-related psychiatric disorders will lead to improved treatments and diagnostic tests - a high priority for the National Institutes of Health.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Arguello, Alexander
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University of Pennsylvania
Schools of Medicine
United States
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Zhao, Ying-Tao; Kwon, Deborah Y; Johnson, Brian S et al. (2018) Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains. Genome Res 28:933-942
Johnson, Brian S; Zhao, Ying-Tao; Fasolino, Maria et al. (2017) Biotin tagging of MeCP2 in mice reveals contextual insights into the Rett syndrome transcriptome. Nat Med 23:1203-1214
Hu, Peng; Fabyanic, Emily; Kwon, Deborah Y et al. (2017) Dissecting Cell-Type Composition and Activity-Dependent Transcriptional State in Mammalian Brains by Massively Parallel Single-Nucleus RNA-Seq. Mol Cell 68:1006-1015.e7
Kwon, Deborah Y; Zhao, Ying-Tao; Lamonica, Janine M et al. (2017) Locus-specific histone deacetylation using a synthetic CRISPR-Cas9-based HDAC. Nat Commun 8:15315