The contribution of epigenetic factors in the etiology of neurodevelopmental disorders has become widely recognized. However, an understanding of the role of epigenetics in neurodevelopmental disorders requires understanding how epigenetic modifications are involved in brain development. Knowledge of the nature of the epigenetic landscape of human neurodevelopment is essential for interpretation of epigenetic findings from neurodevelopmental disorders such as autism, schizophrenia, major depression, and anxiety disorder. In this study, we will investigate the epigenetic landscape of the brain throughout development. We will characterize those epigenetic signatures that define neurodevelopmental trajectories, which are conserved in human and non-human primates. Specifically, we will characterize neuronal DNA methylation patterns at single CpG resolution within dorsal lateral prefrontal cortex and nucleus accumbens of human and rhesus macaque, using state of the art ultra high throughput sequencing technology. Among the known epigenetic marks, DNA methylation marks are the most stable postmortem, and as such allow investigation of the role of epigenetics in conferring long lasting gene expression changes within target neurodevelopmental trajectories. These data will enhance our knowledge of the regulatory mechanisms underlying primate neurodevelopment. By identifying genes subject to epigenetic neurodevelopmental regulation, this study will provide a framework for interpretation of findings from investigations of neurodevelopmental disorders. These findings will be examined in schizophrenic subjects to identify aberrations in establishment or maintenance, or environmentally mediated alterations in DNA methylation patterns associated with risk for schizophrenia disorder.

Public Health Relevance

The goal of this project is to understand the molecular biology of primate brain development by mapping the regulatory mechanisms that control genes involved in brain development. This knowledge will inform our understanding of how abnormal brain development can lead to neurodevelopmental disorders such as autism and schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
7R01MH094774-03
Application #
8504530
Study Section
Special Emphasis Panel (ZMH1-ERB-M (02))
Program Officer
Friedman-Hill, Stacia
Project Start
2011-09-15
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$781,286
Indirect Cost
$280,212
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Haghighi, Fatemeh; Xin, Yurong; Chanrion, Benjamin et al. (2014) Increased DNA methylation in the suicide brain. Dialogues Clin Neurosci 16:430-8