Suicide is a major public health concern. Although attempts have been made to investigate the neurobiology of suicide, the precise molecular mechanisms associated with this disorder are still unclear. It has been proposed that mood disorders/suicide result from an inability of the brain to make appropriate adaptive responses to environmental stimuli. Epigenomic processes are essential not only for normal cellular development and differentiation, but also critical for regulation of gene function through non-mutagenic mechanisms. DNA methylation is the major epigenetic approach for modulating the gene-environment interaction through alterations of promoter regulatory sequences and is associated with stable and adaptive changes in brain functions. In our previous studies, we have consistently shown that the expression of genes involved in neural and structural plasticity is significantly down-regulated in the postmortem brain of suicide subjects, suggesting that altered gene expression may be crucial in the etiology of suicide. Interestingly, a large number of genes exhibit an inverse correlation between the degree of methylation and the magnitude of gene expression. Therefore, the possibility that epigenetic modifications of DNA causing such alterations in the expression of certain genes in brain of suicide subjects, cannot be ruled out. In fact, research in the area of epigenomic regulation of gene expression has led to the hypothesis that the polygenic nature of complex psychiatric disorders might indicate that a common pathway is involved in the dysregulation of multiple genes through an epigenomic mechanism. Although still in infancy, recent evidence suggests that epigenetic factors may play a key role in the pathogenic mechanisms of psychiatric illnesses. To investigate whether epigenetic modifications of DNA play any role in suicidal behavior, we are proposing a pilot study to investigate large- scale epigenetic profiling in the prefrontal cortex of a cohort comprising depressed suicide, non-suicide depressed and well-matched non-psychiatric healthy normal comparison subjects. More specifically, we will examine the following: 1) DNA methylation pattern at the promoters of all known protein-coding genes;2) confirm microarray results using sodium bisulfite modification-based mapping of metC/CAEC/T ratios in the CpG sites;3) use a network-based approach to test the modularity of the epigenomic data;and 4) combined analysis of epigenomic profiles and global gene expression data. To further replicate the DNA methylation study, in another cohort of depressed suicide and healthy comparison subjects, we propose to follow-up 10 to 15 promoters of genes that exhibit the largest epigenomic differences between depressed suicide and normal control subjects. To our knowledge, the proposed research will be the first of its kind in suicide research, and will likely identify major epigenetic modifications in the suicide brain. The proposed studies will also pave the way for our future epigenetic studies and will be crucial for identifying the etiological and pathogenic mechanisms of suicide.

Public Health Relevance

Our proposed study will yield important information on the neurobiology of suicide, which may eventually lead to better treatment and possibly prevention of suicide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH091509-02
Application #
8089539
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Koester, Susan E
Project Start
2010-06-15
Project End
2013-10-31
Budget Start
2011-05-01
Budget End
2013-10-31
Support Year
2
Fiscal Year
2011
Total Cost
$194,288
Indirect Cost
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Dwivedi, Yogesh (2016) Pathogenetic and therapeutic applications of microRNAs in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 64:341-8
Dwivedi, Yogesh (2014) Emerging role of microRNAs in major depressive disorder: diagnosis and therapeutic implications. Dialogues Clin Neurosci 16:43-61
Smalheiser, Neil R; Lugli, Giovanni; Zhang, Hui et al. (2014) Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects. PLoS One 9:e86469
Dwivedi, Yogesh (2013) microRNAs as Biomarker in Depression Pathogenesis. Ann Psychiatry Ment Health 1:1003
Dwivedi, Yogesh (2013) Involvement of brain-derived neurotrophic factor in late-life depression. Am J Geriatr Psychiatry 21:433-49
Smalheiser, Neil R; Lugli, Giovanni; Rizavi, Hooriyah S et al. (2012) MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects. PLoS One 7:e33201
Smalheiser, Neil R; Lugli, Giovanni; Rizavi, Hooriyah S et al. (2011) MicroRNA expression in rat brain exposed to repeated inescapable shock: differential alterations in learned helplessness vs. non-learned helplessness. Int J Neuropsychopharmacol 14:1315-25
Dwivedi, Yogesh (2011) Evidence demonstrating role of microRNAs in the etiopathology of major depression. J Chem Neuroanat 42:142-56