It is well established that environmental factors, such as early life adversity and adult chronic stress, have long-lasting effects on behavior and contribute to the development of psychiatric diseases. Although environmentally-induced epigenetic changes in DNA methylation and chromatin structure at some candidate disease genes have been implicated in the development of disease phenotypes, it is still unknown whether the epigenetic alterations are global or local and if they are a cause or a consequence of the phenotype. Our recent work with genome-wide epigenetic profiling of homogenous populations of hippocampal neurons showed that a wide range of environmental insults alter the epigenome at discrete domains. These epigenomic "hotspots" are characterized by specific features that distinguish them from the rest of the genome. The epigenomic hotspots are typically intragenic, located preferentially in exons, and found in introns of genes involved in synaptic plasticity and gene regulatory processes. We hypothesize that the presence of these epigenomic domains is evolutionarily beneficial because it allows rapid methylation changes at neuroplasticity genes in response to environmental inputs, which ultimately leads to adaptive changes in gene expression and behavior. However, sustained adverse environmental inputs can lock these environmentally-sensitive epigenomic domains into an irreversible state, resulting in loss of plasticity and maladaptive behavior. The discovery of these unique epigenomic domains has both basic and translation implications because they can mechanistically link environmental factors to the resultant behavioral phenotypes. Furthermore, they may be used as biomarkers, to assess prior stress exposure, and as pharmacological targets, to prevent and reverse adversity/stress induced psychopathology. To address these possibilities we propose to investigate the regulatory (Aim 1), neurobiological (Aim 2), and the potential diagnostic/clinical importance (Aim 3) of the identified epigenomic domains.

Public Health Relevance

Environmental adversity and stress have long-lasting effects on behavior and contribute to the development of psychiatric diseases but the underlying molecular mechanism by which this occurs is not known. We identified a unique genomic domain that undergoes secondary DNA modifications (e.g. epigenetic changes) by adverse and stressful environments. The proposed work will causally link the environmental risk factors to the resulting behavioral phenotypes via the identified epigenomic hotspots as well as explore the possibility of their use as a diagnostic tool in the detection of disease risk and as a therapeutic target in the treatment of psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH103102-01
Application #
8639733
Study Section
Special Emphasis Panel (ZMH1-ERB-M (07))
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2013-09-26
Project End
2017-07-31
Budget Start
2013-09-26
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$334,830
Indirect Cost
$134,830
Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065