Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques
Open Access
- 2 August 2010
- journal article
- Published by Wiley in Genes, Brain and Behavior
- Vol. 9 (6), 575-582
- https://doi.org/10.1111/j.1601-183x.2010.00588.x
Abstract
Epigenetic mechanisms may moderate genetic and environmental risk (G×E) for mood disorders. We used an experimental rhesus macaque model of early life stress to test whether epigenetic regulation of serotonin transporter (5‐HTT) may contribute to G×E interactions that influence behavior and emotion. We hypothesized that peripheral blood mononuclear cell (PBMC) DNA methylation within an 800 bp cytosine–phosphate–guanosine (CpG) island that overlaps with the 5‐HTT transcription initiation start site, a hypothesized model of the same genomic region in brain tissue, would mediate or moderate the effects of early life stress and a functional 5‐HTT promoter polymorphism (rh5‐HTTLPR) on two outcomes: PBMC 5‐HTT expression and behavioral stress reactivity. Eighty‐seven infant rhesus macaques (3–4 months of age) were either mother reared in large social groups (n = 70) or nursery reared (n = 17). During a maternal/social separation, infants' blood was sampled and behavioral stress reactivity recorded. PBMC DNA and RNA samples were used to determine rh5‐HTTLPR genotype, 5‐HTT mRNA expression using quantitative reverse transcription polymerase chain reaction (qRT‐PCR) and 5‐HTT CpG methylation status using sodium bisulfite pyrosequencing. Consistent with human data, carriers of the low‐expressing rh5‐HTTLPR alleles exhibited higher mean 5‐HTT CpG methylation, which was associated with lower PBMC 5‐HTT expression. Higher 5‐HTT CpG methylation, but not rh5‐HTTLPR genotype, exacerbated the effects of early life stress on behavioral stress reactivity in infants. 5‐HTT CpG methylation may be an important regulator of 5‐HTT expression early in development and may contribute to the risk for mood disorders observed in ‘high‐risk’5‐HTTLPR carriers.Keywords
This publication has 44 references indexed in Scilit:
- Methylation at SLC6A4 is linked to family history of child abuse: An examination of the Iowa Adoptee sampleAmerican Journal Of Medical Genetics Part B-Neuropsychiatric Genetics, 2010
- Serotonin pathway gene–gene and gene–environment interactions influence behavioral stress response in infant rhesus macaquesDevelopment and Psychopathology, 2010
- Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of DepressionJAMA, 2009
- Reported childhood abuse is associated with low serotonin transporter binding in vivo in major depressive disorderSynapse, 2009
- Lasting Epigenetic Influence of Early-Life Adversity on the BDNF GeneBiological Psychiatry, 2009
- Iron deficiency anemia and affective response in rhesus monkey infantsDevelopmental Psychobiology, 2008
- MAOA methylation is associated with nicotine and alcohol dependence in womenAmerican Journal Of Medical Genetics Part B-Neuropsychiatric Genetics, 2008
- Epigenomic Profiling Reveals DNA-Methylation Changes Associated with Major PsychosisAmerican Journal of Human Genetics, 2008
- The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption StudiesAmerican Journal Of Medical Genetics Part B-Neuropsychiatric Genetics, 2007
- Epigenetic programming by maternal behaviorNature Neuroscience, 2004