A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide.
Editing of the pre-mRNA for the serotonin receptor 2C (5-HT2CR) by site-specific adenosine deamination (A-to-I pre-mRNA editing) substantially increases the functional plasticity of this key neurotransmitter receptor and is thought to contribute to homeostatic mechanisms in neurons. 5-HT2CR mRNA editing generates up to 24 different receptor isoforms. The extent of editing correlates with 5-HT2CR functional activity: more highly edited isoforms exhibit the least function. Altered 5-HT2CR editing has been reported in postmortem brains of suicide victims. We report a comparative analysis of the connections among 5-HT2CR editing, genome-wide gene expression and DNA methylation in suicide victims, individuals with major depressive disorder and non-psychiatric controls. The results confirm previous findings of an overrepresentation of highly edited mRNA variants (which encode hypoactive 5-HT2CR receptors) in the brains of suicide victims. A large set of genes for which the expression level is associated with editing was detected. This signature set of editing-associated genes is significantly enriched for genes that are involved in synaptic transmission, genes that are preferentially expressed in neurons, and genes whose expression is correlated with the level of DNA methylation. Notably, we report that the link between 5-HT2CR editing and gene expression is disrupted in suicide victims. The results suggest that the postulated homeostatic function of 5-HT2CR editing is dysregulated in individuals who committed suicide.
Department of Genetics and Genomic Sciences and.
Antonio Fabio
AF
Di Narzo
Department of Psychiatry, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA James J. Peters VA Medical Center, Bronx, NY, USA.
Alexey
A
Kozlenkov
Department of Genetics and Genomic Sciences and Department of Psychiatry, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA James J. Peters VA Medical Center, Bronx, NY, USA.
Panos
P
Roussos
Department of Genetics and Genomic Sciences and.
Ke
K
Hao
Department of Psychiatry, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Yasmin
Y
Hurd
Department of Psychiatry, Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
David A
DA
Lewis
Department of Psychiatry, Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
Etienne
E
Sibille
Department of Psychiatry, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA James J. Peters VA Medical Center, Bronx, NY, USA.
Larry J
LJ
Siever
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA.
Eugene
E
Koonin
Department of Psychiatry, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA James J. Peters VA Medical Center, Bronx, NY, USA stella.dracheva@mssm.edu.
Stella
S
Dracheva
D001344:Autopsy; D016022:Case-Control Studies; D019175:DNA Methylation; D003865:Major Depressive Disorder / Q000235:genetics*; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism*; D017393:RNA Editing; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics* / Q000378:metabolism; D013405:Suicide
D044405:Receptor, Serotonin, 5-HT2C