Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques

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.

Life course socioeconomic status and DNA methylation in genes related to stress reactivity and inflammation: The multi-ethnic study of atherosclerosis

“…56 Rodent and primate studies examining various stress exposures, including restraint stress, social defeat, and maternal separation, have found associations of these exposures with DNAm in genes that encode proteins involved in functioning of the HPA axis, including AVP, 19 BDNF, 20,21 CRF, 22 FKBP5, 23 GR, [24][25][26] and SLC6A4. 31,34 Similarly, previous research in humans has found that a range of stress-related exposures, including childhood abuse, in-utero exposure to maternal depression, acute stress exposure (the Trier Social Stress Test), and history of major depressive disorder, are associated with alterations in DNAm in stress-related genes, such as GR, [27][28][29] OXTR, 30 and SLC6A4, 32,33 while exposure to post-traumatic stress disorder (PTSD) is associated with DNAm in a number of genes related to inflammation, including CD1D, CCL1, F8, IL8, KLRG1, LTA4H, NLRP12, PYDC1, SLAMF7, TLR1, and TLR3. 35 In addition to stress exposure, SES may be linked to DNAm through other pathways, such as negative affect, household or occupational exposure to carcinogens and pathogens, and diet and physical activity.…”

“…We selected candidate genes based on the results of prior work in rodents, primates, and humans, which found that exposure to various psychosocial stressors was associated with DNAm in genes related to stress reactivity, including AVP, 19 BDNF, 20,21 CRF, 22 FKBP5, 23 GR, [24][25][26][27][28][29] OXTR, 30 and SLC6A4, [31][32][33][34] and inflammation, including CD1D, CCL1, F8, IL8, KLRG1, LTA4H, NLRP12, PYDC1, SLAMF7, TLR1, and TLR3. 35 Stress reactivity and inflammation have been hypothesized to mediate the impact of social circumstances on health and are therefore reasonable candidates for investigation of SES effects on DNAm processes.…”

The serotonergic system in mood disorders and suicidal behaviour

“…Perhaps other promoter variants play a major role and override this relationship. Another mechanism is epigenetic and it has been shown that DNA methylation can be related to gene expression and thereby transporter binding [94]. This may explain how childhood adversity can lead to less transporter binding in the brain in adulthood as has been shown in non-human primates [95] and in depressed patients reporting childhood abuse [96].…”

Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

“…For instance, rhesus monkeys reared in a nursery, displayed higher SERT methylation and increased separation anxiety during maternal-social separation compared with mother-reared infants. 138 In humans, using peripheral cells, several studies indicated that early stress was associated with altered levels of SERT promoter methylation. [139][140][141][142][143] In turn, we observed that SERT promoter methylation in the white blood cells of adults was associated with lower in vivo measures of brain 5-HT synthesis in the lateral orbitofrontal cortex and greater childhood aggression.…”