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Ernst et al's Alternative Splicing, Methylation State, and Expression Profile of Tropomyosin-Related

Ernst et al's Alternative Splicing, Methylation State, and Expression Profile of Tropomyosin-Related

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ORIGINAL ARTICLE Alternative Splicing, Methylation State, and Expression Profile of Tropomyosin-Related Kinase B in the Frontal Cortex of Suicide Completers Carl Ernst, MSc; Vesselina Deleva, MSc; Xiaoming Deng, MD; Adolfo Sequeira, PhD; Amanda Pomarenski, BSc; Tim Klempan, PhD; Neil Ernst, MSc; Remi Quirion, PhD; Alain Gratton, PhD; Moshe Szyf, PhD; Gustavo Turecki, MD, PhD Context : Although most of the effort to understand the neurobiology of depressive states and suicide has fo- cused on neuronal processes, recent studies suggest that astroglial dysfunction may play an important role. A truncated variant of the tropomyosin-related kinase B (TrkB.T1) is expressed in astrocytes, and brain-derived neurotrophic factor–TrkB signaling has been linked to mood disorders. Objective : To test the hypothesis that TrkB.T1 expres- sion is downregulated in suicide completers and that this downregulation is mediated by an epigenetic process. Design : Postmortem case-control study. Patients, Setting, and Main Outcome Measures : Thirty-nine French Canadian men underwent screen- ing at the Douglas Hospital Research Institute using the HG-U133 plus 2 microarray chip. Nine frontal cortical regions and the cerebellum were assessed using a micro- array screening approach for extreme expression differ- ences across subjects and a conventional screening ap- proach. Results were validated by quantitative polymerase chain reaction and Western blot analyses. Animal ex- periments were performed to control for drug and alco- hol effects. Genetic and epigenetic studies were per- formed by means of direct sequencing and bisulfite mapping. Results : We found that 10 of 28 suicide completers (36%) demonstrated significant decreases in different probe sets specific to TrkB.T1 in Brodmann areas 8 and 9. These findings were generalizable to other frontal regions but not to the cerebellum. The decrease in TrkB expression was specific to the T1 splice variant. Our results were not accounted for by substance comorbidity or by reduc- tion in astrocyte number. We found no effect of genetic variation in a 2500–base pair promoter region or at rel- evant splice junctions; however, we detected an effect of methylation state at particular CpG dinucleotides on TrkB.T1 expression. Conclusion : A reduction of TrkB.T1 expression in the frontal cortex of a subpopulation of suicide completers is associated with the methylation state of the promoter region. Arch Gen Psychiatry. 2009;66(1):22-32 S UICIDE IS MOST OFTEN ASSO - ciated with depressed mood and hopelessness and is a leading cause of death in many regions of the world. 1-6 Although much of the effort to under- stand the biological mechanisms of these moodstateshascenteredonneuronalpro- cesses, some recent studies have sug- gestedthatastroglialdysfunctionmayplay an important role.
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