Genomic and epigenetic evidence for oxytocin receptor deficiency in autism

<p>Abstract</p> <p>Background</p> <p>Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders.</p> <p>Methods</p> <p>We describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR).</p> <p>Results</p> <p>Our analysis revealed a genomic deletion containing the oxytocin receptor gene, <it>OXTR </it>(MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate <it>OXTR </it>expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that <it>OXTR </it>mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls.</p> <p>Conclusion</p> <p>Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of <it>OXTR </it>in the development of the disorder.</p> <p>See the related commentary by Gurrieri and Neri: <url>http://www.biomedcentral.com/1741-7015/7/63</url></p

DNA methylation patterns of behavior-related gene promoter regions dissect the gray wolf from domestic dog breeds

A growing body of evidence highlights the relationship between epigenetics, especially DNA methylation, and population divergence as well as speciation. However, little is known about how general the phenomenon of epigenetics-wise separation of different populations is, or whether population assignment is, possible based on solely epigenetic marks. In the present study, we compared DNA methylation profiles between four different canine populations: three domestic dog breeds and their ancestor the gray wolf. Altogether, 79 CpG sites constituting the 65 so-called CpG units located in the promoter regions of genes affecting behavioral and temperamental traits (COMT, HTR1A, MAOA, OXTR, SLC6A4, TPH1, WFS1)-regions putatively targeted during domestication and breed selection. Methylation status of buccal cells was assessed using EpiTYPER technology. Significant inter-population methylation differences were found in 52.3% of all CpG units investigated. DNA methylation profile-based hierarchical cluster analysis indicated an unambiguous segregation of wolf from domestic dog. In addition, one of the three dog breeds (Golden Retriever) investigated also formed a separate, autonomous group. The findings support that population segregation is interrelated with shifts in DNA methylation patterns, at least in putative selection target regions, and also imply that epigenetic profiles could provide a sufficient basis for population assignment of individuals

Dynamic changes in DNA methylation of stress-associated genes (OXTR, BDNF) after acute psychosocial stress

Environmentally induced epigenetic alterations are related to mental health. We investigated quantitative DNA methylation status before and after an acute psychosocial stressor in two stress-related genes: oxytocin receptor (OXTR) and brain-derived neurotrophic factor (BDNF ). The cross sectional study took place at the Division of Theoretical and Clinical Psychobiology, University of Trier, Germany and was conducted from February to August 2009. We included 83 participants aged 61-67 years. Thereof, 76 participants completed the full study procedure consisting of blood sampling before (pre-stress), 10 min after (post-stress) and 90 min after (follow-up) the Trier social stress test. We assessed quantitative DNA methylation of whole-blood cells using Sequenom EpiTYPER. Methylation status differed between sampling times in one target sequence of OXTR (P>0.001): methylation increased from pre- to post-stress (P=0.009) and decreased from post-stress to follow-up (P>0.001). This decrease was also found in a second target sequence of OXTR (P=0.034), where it lost statistical significance when blood cell count was statistically controlled. We did not detect any time-associated differences in methylation status of the examined BDNF region. The results suggest a dynamic regulation of DNA methylation in OXTR-which may in part reflect changes in blood cell composition-but not BDNF after acute psychosocial stress. This may enhance the understanding of how psychosocial events alter DNA methylation and could provide new insights into the etiology of mental disorders