Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Recent studies on humans and macaque monkeys showed that higher methylation levels of the 5-HTT gene were associated with stronger effects of stress.
“recent studies on humans and macaque monkeys showed that higher methylation levels of the 5-HTT gene were associated with stronger effects of stress 133, 134.”
From Resilience in mental health: linking psychological and neurobiological perspectives. (2013) · cites this paper as [133]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., et al. (2003) · Science · doi:10.1126/science.1083968 · Cited by 8,120 · see citing works
Epigenetic programming by maternal behavior
Weaver, I. C. G., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., Dymov, S., Szyf, M., & Meaney, M. J. (2004) · Nature Neuroscience · doi:10.1038/nn1276 · Cited by 6,177 · see citing works
CpG-rich islands and the function of DNA methylation
Bird, A. P. (1986) · Nature · doi:10.1038/321209a0 · Cited by 3,777 · see citing works
Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse
McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonté, B., Szyf, M., Turecki, G., & Meaney, M. J. (2009) · Nature Neuroscience · doi:10.1038/nn.2270 · Cited by 3,531 · see citing works
Allelic Variation of Human Serotonin Transporter Gene Expression
Heils, A., Teufel, A., Petri, S., Stöber, G., Riederer, P., Bengel, D., & Lesch, K. P. (1996) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1996.66062621.x · Cited by 2,221 · see citing works
The Role of DNA Methylation in Mammalian Epigenetics
Jones, P. A., & Takai, D. (2001) · Science · doi:10.1126/science.1063852 · Cited by 2,063 · see citing works
Risch, N., Herrell, R., Lehner, T., Liang, K.-Y., Eaves, L., Hoh, J., Griem, A., Kovacs, M., Ott, J., & Merikangas, K. R. (2009) · JAMA · doi:10.1001/jama.2009.878 · Cited by 1,655 · see citing works
Oberlander, T. F., Weinberg, J., Papsdorf, M., Grunau, R., Misri, S., & Devlin, A. M. (2008) · Epigenetics · doi:10.4161/epi.3.2.6034 · Cited by 1,432 · see citing works
Lasting epigenetic influence of early-life adversity on the BDNF gene
Roth, T. L., Lubin, F. D., Funk, A. J., & Sweatt, J. D. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.11.028 · Cited by 1,273 · see citing works
Early-Life Blockade of the 5-HT Transporter Alters Emotional Behavior in Adult Mice
Ansorge, M. S., Zhou, M., Lira, A., Hen, R., & Gingrich, J. A. (2004) · Science · doi:10.1126/science.1101678 · Cited by 817 · see citing works
Social supports and serotonin transporter gene moderate depression in maltreated children
Kaufman, J., Yang, B., Douglas-Palumberi, H., Houshyar, S., Lipschitz, D. S., Krystal, J. H., & Gelernter, J. E. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404376101 · Cited by 801 · see citing works
Epigenomic Profiling Reveals DNA-Methylation Changes Associated with Major Psychosis
Mill, J., Tang, T., Kaminsky, Z., Khare, T., Yazdanpanah, S., Bouchard, L., Jia, P., Assadzadeh, A., Flanagan, J., Schumacher, A., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.01.008 · Cited by 773 · see citing works
Spl elements protect a CpG island from de novo methylation
Brandeis, M., Frank, D., Keshet, I., Siegfried, Z., Mendelsohn, M. M., Names, A., Temper, V., Razin, A., & Cedar, H. (1994) · Nature · doi:10.1038/371435a0 · Cited by 705 · see citing works
DNA methylation analysis by pyrosequencing
Tost, J., & Gut, I. G. (2007) · Nature Protocols · doi:10.1038/nprot.2007.314 · Cited by 665 · see citing works
Sp1 sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island.Preprint
Macleod, D., Charlton, J., Mullins, J. J., & Bird, A. P. (1994) · Genes & Development · doi:10.1101/gad.8.19.2282 · Cited by 596 · see citing works
Gene×environment interactions at the serotonin transporter locus
Munafò, M. R., Durrant, C., Lewis, G., & Flint, J. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.06.009 · Cited by 576 · see citing works
DNA Methylation Analysis by Pyrosequencing
Busato, F., & Tost, J. (2014) · Springer eBooks · doi:10.1007/978-1-4614-6418-1_799-1 · Cited by 500 · see citing works
Charney, D. S., & Manji, H. K. (2004) · Science s STKE · doi:10.1126/stke.2252004re5 · Cited by 426 · see citing works
Zalsman, G., Huang, Y.-Y., Oquendo, M. A., Burke, A. K., Hu, X.-Z., Brent, D. A., Ellis, S. P., Goldman, D., & Mann, J. J. (2006) · American Journal of Psychiatry · doi:10.1176/ajp.2006.163.9.1588 · Cited by 371 · see citing works
Self-citationChampoux, M. C., Bennett, A. J., Shannon, C., Higley, J. D., Lesch, K., & Suomi, S. J. (2002) · Molecular Psychiatry · doi:10.1038/sj.mp.4001157 · Cited by 367 · see citing works
Lower Serotonin Transporter Binding Potential in the Human Brain During Major Depressive Episodes
Parsey, R. V., Hastings, R., Oquendo, M. A., Huang, Y., Simpson, N. R., Arcement, J., Huang, Y. H., Ogden, R. T., Heertum, R. L. V., Arango, V., et al. (2006) · American Journal of Psychiatry · doi:10.1176/appi.ajp.163.1.52 · Cited by 310 · see citing works
Self-citationNeonatal Antidepressant Exposure has Lasting Effects on Behavior and Serotonin Circuitry
Maciąg, D., Simpson, K. L., Coppinger, D., Lu, Y., Wang, Y., Lin, R. C. S., & Paul, I. A. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300823 · Cited by 302 · see citing works
Philibert, R. A., Sandhu, H., Hollenbeck, N., Gunter, T., Adams, W., & Madan, A. (2008) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30657 · Cited by 300 · see citing works
Social Adversity, the Serotonin Transporter (5-HTTLPR) Polymorphism and Major Depressive Disorder
Surtees, P. G., Wainwright, N. W. J., Willis-Owen, S. A. G., Luben, R., Day, N. E., & Flint, J. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.07.014 · Cited by 265 · see citing works
Barr, C. S., Newman, T. K., Lindell, S. G., Shannon, C., Champoux, M., Lesch, K., Suomi, S. J., Goldman, D. A., & Higley, J. D. (2004) · Archives of General Psychiatry · doi:10.1001/archpsyc.61.11.1146 · Cited by 259 · see citing works
Stein, M. B., Schork, N. J., & Gelernter, J. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301422 · Cited by 247 · see citing works
Beach, S. R. H., Brody, G. H., Todorov, A. A., Gunter, T. D., & Philibert, R. A. (2009) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31028 · Cited by 229 · see citing works
Lee, J.-H., Kim, H. J., Kim, J. G., Ryu, V., Kim, B.-T., Kang, D. W., & Jahng, J. W. (2007) · Neuroscience Research · doi:10.1016/j.neures.2007.01.008 · Cited by 228 · see citing works
Hranilovic, D., Stefulj, J., Schwab, S., Borrmann-Hassenbach, M., Albus, M., Jernej, B., & Wildenauer, D. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.01.029 · Cited by 224 · see citing works
Cicchetti, D., Rogosch, F. A., & Sturge-Apple, M. L. (2007) · Development and Psychopathology · doi:10.1017/s0954579407000600 · Cited by 204 · see citing works
Serotonin transporter mRNA levels are associated with the methylation of an upstream CpG island
Philibert, R. A., Madan, A., Andersen, A. M., Cadoret, R. J., Packer, H., & Sandhu, H. K. (2006) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30414 · Cited by 191 · see citing works
Heinz, A., Higley, J. D., Gorey, J. G., Saunders, R. C., Jones, D. W., Hommer, D. W., Zajicek, K. B., Suomi, S. J., Lesch, K., Weinberger, D. R., et al. (1998) · American Journal of Psychiatry · doi:10.1176/ajp.155.8.1023 · Cited by 171 · see citing works
MAOA methylation is associated with nicotine and alcohol dependence in women
Philibert, R. A., Gunter, T. D., Beach, S. R. H., Brody, G. H., & Madan, A. (2008) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30778 · Cited by 162 · see citing works
Capitanio, J. P., Mendoza, S. P., Mason, W. A., & Maninger, N. (2005) · Developmental Psychobiology · doi:10.1002/dev.20067 · Cited by 153 · see citing works
Self-citationOlsson, C. A., Foley, D. L., Parkinson-Bates, M., Byrnes, G., McKenzie, M., Patton, G. C., Morley, R., Anney, R. J. L., Craig, J. M., & Saffery, R. (2010) · Biological Psychology · doi:10.1016/j.biopsycho.2009.12.003 · Cited by 137 · see citing works
Ichise, M., Vines, D. C., Gura, T., Anderson, G. M., Suomi, S. J., Higley, J. D., & Innis, R. B. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.5199-05.2006 · Cited by 134 · see citing works
Kinnally, E. L., Tarara, E. R., Mason, W. A., Mendoza, S. P., Abel, K., Lyons, L. A., & Capitanio, J. P. (2009) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2009.00533.x · Cited by 125 · see citing works
Self-citationMiller, J. M., Kinnally, E. L., Ogden, R. T., Oquendo, M. A., Mann, J. J., & Parsey, R. V. (2009) · Synapse · doi:10.1002/syn.20637 · Cited by 107 · see citing works
Self-citationIron deficiency anemia and affective response in rhesus monkey infants
Golub, M. S., Hogrefe, C. E., Widaman, K. F., & Capitanio, J. P. (2008) · Developmental Psychobiology · doi:10.1002/dev.20345 · Cited by 92 · see citing works
Self-citationNursery Rearing and Biobehavioral Organization
Capitanio, J. P., Mason, W. A., Mendoza, S. P., DelRosso, L., & Roberts, J. A. (2006) · Springer eBooks · doi:10.1007/978-0-387-25640-5_11 · Cited by 71 · see citing works
Self-citationKinnally, E. L., Lyons, L. A., Abel, K., Mendoza, S. P., & Capitanio, J. P. (2007) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2007.00383.x · Cited by 57 · see citing works
Self-citationUebelhack, R., Franke, L., Herold, N., Plotkin, M., Amthauer, H., & Felix, R. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.06.004 · Cited by 52 · see citing works
Kinnally, E. L., Karere, G. M., Lyons, L. A., Mendoza, S. P., Mason, W. A., & Capitanio, J. P. (2010) · Development and Psychopathology · doi:10.1017/s0954579409990241 · Cited by 41 · see citing works
Self-citationCupello, A., Albano, C., Gatta, E., et al. (2008) · Neurochemical Research · doi:10.1007/s11064-008-9764-z · Cited by 11 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- Heils A Teufel A Petri S Stober G Riederer P Bengel D Lesch KP Allelic variation of human serotonin transporter gene expression Journal of Neurochemistry 1996 2621 2624 8632190
- Lu J Le François B Burns AM Stockmeier CA Austin MC Overholser JC Jurjus G Meltzer HY Albert PR Increased DNA methylation of the 5-HT1A receptor promoter in suicide brain. CINP 50th Meeting, July 14–17, Munich, Germany International Journal of Neuropsychopharmacology 2008 11 Suppl. 1 105
- Nemeroff C Early-Life Adversity, CRF Dysregulation, and Vulnerability to Mood and Anxiety Disorders Psychopharmacology Bulletin 2004 38 14 20 15278013
Cited by
Sorted by citations
Moylan, S., Maes, M., Wray, N. R., & Berk, M. (2013) · Molecular Psychiatry · doi:10.1038/mp.2012.33 · Cited by 529 · see citing works
Resilience in mental health: linking psychological and neurobiological perspectives.
Rutten, B. P. F., Hammels, C., Geschwind, N., Menne‐Lothmann, C., Pishva, E., Schruers, K., van den Hove, D., Kenis, G., van Os, J., & Wichers, M. (2013) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12095 · Cited by 418 · see citing works
Maternal separation as a model of brain-gut axis dysfunction
O’Mahony, S. M., Hyland, N. P., Dinan, T. G., & Cryan, J. F. (2011) · Psychopharmacology · doi:10.1007/s00213-010-2010-9 · Cited by 415 · see citing works
Telomere length and early severe social deprivation: linking early adversity and cellular aging
Drury, S. S., Theall, K., Gleason, M. M., Smyke, A. T., De Vivo, I., Wong, J. Y. Y., Fox, N. A., Zeanah, C. H., & Nelson, C. A. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.53 · Cited by 316 · see citing works
Early-life experience, epigenetics, and the developing brain
Kundakovic, M., & Champagne, F. A. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2014.140 · Cited by 304 · see citing works
Association of SLC6A4 methylation with early adversity, characteristics and outcomes in depression
Kang, H.-J., Kim, J.-M., Stewart, R., Kim, S.-Y., Bae, K.-Y., Kim, S.-W., Shin, I.-S., Shin, M.-G., & Yoon, J.-S. (2013) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2013.01.006 · Cited by 254 · see citing works
The serotonergic system in mood disorders and suicidal behaviour
Mann, J. J. (2013) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2012.0537 · Cited by 235 · see citing works
Self-citationThe reciprocal interaction between serotonin and social behaviour
Kiser, D., SteemerS, B., Branchi, I., & Homberg, J. R. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.12.009 · Cited by 214 · see citing works
Ouellet-Morin, I., Wong, C. C. Y., Danese, A., Pariante, C. M., Papadopoulos, A. S., Mill, J., & Arseneault, L. (2013) · Psychological Medicine · doi:10.1017/s0033291712002784 · Cited by 207 · see citing works
Uddin, M., Koenen, K. C., Aiello, A. E., Wildman, D. E., de los Santos, R., & Galea, S. (2011) · Psychological Medicine · doi:10.1017/s0033291710001674 · Cited by 174 · see citing works
Provenzi, L., Giorda, R., Beri, S., & Montirosso, R. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.08.021 · Cited by 139 · see citing works
The age-dependent effects of selective serotonin reuptake inhibitors in humans and rodents: a review
Olivier, J. D. A., Blom, T., Arentsen, T., & Homberg, J. R. (2011) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.09.013 · Cited by 131 · see citing works
Miller, J. M., Hesselgrave, N., Ogden, R. T., Sullivan, G. M., Oquendo, M. A., Mann, J. J., & Parsey, R. V. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.01.024 · Cited by 102 · see citing works
Self-citationAn epigenome-wide DNA methylation study of PTSD and depression in World Trade Center responders
Kuan, P.-F., Waszczuk, M. A., Kotov, R., Marsit, C. J., Guffanti, G., Gonzalez, A., Yang, X., Koenen, K., Bromet, E., & Luft, B. J. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.130 · Cited by 103 · see citing works
Epigenetics, a key for unlocking complex CNS disorders? Therapeutic implications
Szyf, M. (2015) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2014.01.009 · Cited by 76 · see citing works
Drury, S. S., Sánchez, M. M., & Gonzalez, A. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.10.007 · Cited by 72 · see citing works
Longitudinal associations between BDNF promoter methylation and late-life depression
Kang, H.-J., Kim, J.-M., Bae, K.-Y., Kim, S.-W., Shin, I.-S., Kim, H.-R., Shin, M.-G., & Yoon, J.-S. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.12.035 · Cited by 65 · see citing works
Kentner, A. C., Cryan, J. F., & Brummelte, S. (2019) · Developmental Psychobiology · doi:10.1002/dev.21775 · Cited by 64 · see citing works
Drabe, M., Rullmann, M., Luthardt, J., Boettcher, Y., Regenthal, R., Ploetz, T., Becker, G. A., Patt, M., Schinke, C., Bergh, F. T., et al. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.133 · Cited by 32 · see citing works
- Authors
- Kinnally, E. L., Capitanio, J. P., Leibel, R., Deng, L., LeDuc, C., Haghighi, F., & Mann, J. J.
- Affiliations
- Columbia University (US)
- University of California, Davis (US)
- Corresponding author
- Kinnally, E. L.
- Venue
- Genes, Brain and Behavior
- Publisher
- Wiley
- Published
- 2010-08
- Volume
- 9
- Issue
- 6
- Pages
- 575-582
- ISSN
- 1601-183X (ISSN-L)
- 1601-1848
- PMC
- PMC2921011
- OpenAlex
- W2089883957
- Cited by
- 155
- References
- 44
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 11 · 2017: 15 · 2016: 14 · 2015: 18 · 2014: 14 · 2013: 16 · 2012: 19
- FWCI
- 6.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Genes Brain & Behavior (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R24OD010962)
- National Institute of Mental Health (T32MH015174, P50MH062185)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK052431)
- National Center for Research Resources (P51RR000169, RR 000169, RR019970, S10RR016924, R24RR019970)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- serotonin transporter, DNA methylation, early life stress, gene-environment interaction, 5-HTTLPR, mood disorders, rhesus monkeys, CpG islands, peripheral blood mononuclear cells, infant development
- MeSH terms
- Animals, Animals, Newborn, Behavior, Animal, Female, Gene Expression Regulation, Genotype, Humans, Macaca mulatta, Maternal Deprivation, Polymorphism, Genetic, Promoter Regions, Genetic, Serotonin, Social Behavior, Social Environment, Stress, Psychological, Serotonin Plasma Membrane Transport Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
