Home The epigenetic regulation of synaptic genes contributes to the etiology of autism
Article
Licensed
Unlicensed Requires Authentication

The epigenetic regulation of synaptic genes contributes to the etiology of autism

  • Annamaria Srancikova , Zuzana Bacova and Jan Bakos EMAIL logo
Published/Copyright: May 4, 2021
Become an author with De Gruyter Brill

Abstract

Epigenetic mechanisms greatly affect the developing brain, as well as the maturation of synapses with pervasive, long-lasting consequences on behavior in adults. Substantial evidence exists that implicates dysregulation of epigenetic mechanisms in the etiology of neurodevelopmental disorders. Therefore, this review explains the role of enzymes involved in DNA methylation and demethylation in neurodevelopment by emphasizing changes of synaptic genes and proteins. Epigenetic causes of sex-dependent differences in the brain are analyzed in conjunction with the pathophysiology of autism spectrum disorders. Special attention is devoted to the epigenetic regulation of the melanoma-associated antigen-like gene 2 (MAGEL2) found in Prader-Willi syndrome, which is known to be accompanied by autistic symptoms.


Corresponding author: Jan Bakos, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia; and Institute of Physiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia, E-mail:

Funding source: Grant Agency of Ministry of Education and Slovak Academy of Sciences

Award Identifier / Grant number: VEGA 2/0148/21 VEGA 2/0155/20

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: The review is based on the work supported by the Grant Agency of Ministry of Education and Slovak Academy of Sciences (VEGA 2/0155/20, VEGA 2/0148/21).

  3. Conflict of interest statement: The authors have no conflicts of interest to declare.

References

Aizawa, S. and Yamamuro, Y. (2020). Possible involvement of DNA methylation in hippocampal synaptophysin gene expression during postnatal development of mice. Neurochem. Int. 132: 104587, https://doi.org/10.1016/j.neuint.2019.104587.Search in Google Scholar PubMed

Alex, A.M., Saradalekshmi, K.R., Shilen, N., Suresh, P.A., and Banerjee, M. (2019). Genetic association of DNMT variants can play a critical role in defining the methylation patterns in autism. IUBMB Life 71: 901–907, https://doi.org/10.1002/iub.2021.Search in Google Scholar PubMed

Andari, E., Nishitani, S., Kaundinya, G., Caceres, G.A., Morrier, M.J., Ousley, O., Smith, A.K., Cubells, J.F., and Young, L.J. (2020). Epigenetic modification of the oxytocin receptor gene: implications for autism symptom severity and brain functional connectivity. Neuropsychopharmacology 45: 1150–1158, https://doi.org/10.1038/s41386-020-0610-6.Search in Google Scholar PubMed PubMed Central

Bakos, J., Bacova, Z., Grant, S.G., Castejon, A.M., and Ostatnikova, D. (2015). Are molecules involved in neuritogenesis and axon guidance related to autism pathogenesis? Neuromol. Med. 17: 297–304, https://doi.org/10.1007/s12017-015-8357-7.Search in Google Scholar PubMed

Barnett Burns, S., Almeida, D., and Turecki, G. (2018). The epigenetics of early life adversity: current limitations and possible solutions. Prog. Mol. Biol. Transl. Sci. 157: 343–425, https://doi.org/10.1016/bs.pmbts.2018.01.008.Search in Google Scholar PubMed

Bartolomei, M.S. (2009). Genomic imprinting: employing and avoiding epigenetic processes. Genes Dev. 23: 2124–33, https://doi.org/10.1101/gad.1841409.Search in Google Scholar PubMed PubMed Central

Basil, P., Li, Q., Dempster, E.L., Mill, J., Sham, P.C., Wong, C.C., and McAlonan, G.M. (2014). Prenatal maternal immune activation causes epigenetic differences in adolescent mouse brain. Transl. Psychiatry 4: e434, https://doi.org/10.1038/tp.2014.80.Search in Google Scholar PubMed PubMed Central

Berkel, S., Eltokhi, A., Fröhlich, H., Porras-Gonzalez, D., Rafiullah, R., Sprengel, R., and Rappold, G.A. (2018). Sex hormones regulate SHANK expression. Front. Mol. Neurosci. 11: 337, https://doi.org/10.3389/fnmol.2018.00337.Search in Google Scholar PubMed PubMed Central

Bie, B., Wu, J., Yang, H., Xu, J.J., Brown, D.L., and Naguib, M. (2014). Epigenetic suppression of neuroligin 1 underlies amyloid-induced memory deficiency. Nat. Neurosci. 17: 223–231, https://doi.org/10.1038/nn.3618.Search in Google Scholar PubMed

Bludau, A., Royer, M., Meister, G., Neumann, I.D., and Menon, R. (2019). Epigenetic regulation of the social brain. Trends Neurosci. 42: 471–484, https://doi.org/10.1016/j.tins.2019.04.001.Search in Google Scholar PubMed

Bustos, F.J., Ampuero, E., Jury, N., Aguilar, R., Falahi, F., Toledo, J., Ahumada, J., Lata, J., Cubillos, P., Henríquez, B., et al.. (2017). Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer’s disease mice. Brain 140: 3252–3268, https://doi.org/10.1093/brain/awx272.Search in Google Scholar PubMed PubMed Central

Chao, H.-T., Zoghbi, H.Y., and Rosenmund, C. (2007). MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56: 58–65, https://doi.org/10.1016/j.neuron.2007.08.018.Search in Google Scholar PubMed PubMed Central

Cheng, Y., Li, Z., Manupipatpong, S., Lin, L., Li, X., Xu, T., Jiang, Y.H., Shu, Q., Wu, H., and Jin, P. (2018). 5-Hydroxymethylcytosine alterations in the human postmortem brains of autism spectrum disorder. Hum. Mol. Genet. 27: 2955–2964, https://doi.org/10.1093/hmg/ddy193.Search in Google Scholar PubMed PubMed Central

Cisternas, C.D., Cortes, L.R., Bruggeman, E.C., Yao, B., and Forger, N.G. (2020). Developmental changes and sex differences in DNA methylation and demethylation in hypothalamic regions of the mouse brain. Epigenetics 15: 72–84, https://doi.org/10.1080/15592294.2019.1649528.Search in Google Scholar PubMed PubMed Central

Danoff, J.S., Wroblewski, K.L., Graves, A.J., Quinn, G.C., Perkeybile, A.M., Kenkel, W.M., Lillard, T.S., Parikh, H.I., Golino, H.F., Gregory, S.G., et al.. (2021). Genetic, epigenetic, and environmental factors controlling oxytocin receptor gene expression. Clin. Epigenet. 13: 23, https://doi.org/10.1186/s13148-021-01017-5.Search in Google Scholar PubMed PubMed Central

Dubose, A.J., Smith, E.Y., Yang, T.P., Johnstone, K.A., and Resnick, J.L. (2011). A new deletion refines the boundaries of the murine Prader-Willi syndrome imprinting center. Hum. Mol. Genet. 20: 3461–3466, https://doi.org/10.1093/hmg/ddr262.Search in Google Scholar PubMed PubMed Central

Falougy, H.E., Filova, B., Ostatnikova, D., Bacova and, Z., and Bakos, J. (2019). Neuronal morphology alterations in autism and possible role of oxytocin. Endocr. Regul. 53: 46–54, https://doi.org/10.2478/enr-2019-0006.Search in Google Scholar PubMed

Fan, X.Y., Shi, G., and Zhao, P. (2019). Methylation in Syn and Psd95 genes underlie the inhibitory effect of oxytocin on oxycodone-induced conditioned place preference. Eur. Neuropsychopharmacol. 29: 1464–1475, https://doi.org/10.1016/j.euroneuro.2019.10.010.Search in Google Scholar PubMed

Fan, X.Y., Yang, J.Y., Dong, Y.X., Hou, Y., Liu, S., and Wu, C.F. (2020). Oxytocin inhibits methamphetamine-associated learning and memory alterations by regulating DNA methylation at the Synaptophysin promoter. Addict. Biol. 25: e12697, https://doi.org/10.1111/adb.12697.Search in Google Scholar PubMed

Feil, R. and Fraga, M.F. (2012). Epigenetics and the environment: emerging patterns and implications. Nat. Rev. Genet. 13: 97–109, https://doi.org/10.1038/nrg3142.Search in Google Scholar PubMed

Feng, J., Schroer, R., Yan, J., Song, W., Yang, C., Bockholt, A., Cook, E.H.Jr., Skinner, C., Schwartz, C.E., and Sommer, S.S. (2006). High frequency of neurexin 1β signal peptide structural variants in patients with autism. Neurosci. Lett. 409: 10–13, https://doi.org/10.1016/j.neulet.2006.08.017.Search in Google Scholar PubMed

Feng, J., Zhou, Y., Campbell, S.L., Le, T., Li, E., Sweatt, J.D., Silva, A.J., and Fan, G. (2010). Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat. Neurosci. 13: 423–430, https://doi.org/10.1038/nn.2514.Search in Google Scholar PubMed PubMed Central

Forger, N.G. (2016). Epigenetic mechanisms in sexual differentiation of the brain and behaviour. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 2016 371: 20150114, https://doi.org/10.1098/rstb.2015.0114.Search in Google Scholar PubMed PubMed Central

Fountain, M.D.Jr. and Schaaf, C.P. (2015). MAGEL2 and oxytocin-implications in Prader-Willi syndrome and beyond. Biol. Psychiatry 78: 78–80, https://doi.org/10.1016/j.biopsych.2015.05.006.Search in Google Scholar PubMed

Giovedi, S., Corradi, A., Fassio, A., and Benfenati, F. (2014). Involvement of synaptic genes in the pathogenesis of autism spectrum disorders: the case of synapsins. Front. Pediatry 2: 94. https://doi.org/10.3389/fped.2014.00094.Search in Google Scholar PubMed PubMed Central

Glendining, K.A., Higgins, M.B.A., Fisher, L.C., and Jasoni, C. (2020). Maternal obesity modulates sexually dimorphic epigenetic regulation and expression of leptin receptor in offspring hippocampus. Brain Behav. Immun. 88: 151–160, https://doi.org/10.1016/j.bbi.2020.03.006.Search in Google Scholar PubMed

Graignic-Philippe, R., Dayan, J., Chokron, S., Jacquet, A.Y., and Tordjman, S. (2014). Effects of prenatal stress on fetal and child development: a critical literature review. Neurosci. Biobehav. Rev. 43: 137–162, https://doi.org/10.1016/j.neubiorev.2014.03.022.Search in Google Scholar PubMed

Grayson, D.R. and Guidotti, A. (2018). DNA methylation in animal models of psychosis. Prog. Mol. Biol. Transl. Sci. 157: 105–132, https://doi.org/10.1016/bs.pmbts.2017.12.012.Search in Google Scholar PubMed PubMed Central

Gregg, C., Zhang, J., Weissbourd, B., Luo, S., Schroth, G.P., Haig, D., and Dulac, C. (2010). High-resolution analysis of parent-of-origin allelic expression in the mouse brain. Science 329: 643–648, https://doi.org/10.1126/science.1190830.Search in Google Scholar PubMed PubMed Central

Gregory, S.G., Connelly, J.J., Towers, A.J., Johnson, J., Biscocho, D., Markunas, C.A., Lintas, C., Abramson, R.K., Wright, H.H., Ellis, P., et al.. (2009). Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med. 7: 62, https://doi.org/10.1186/1741-7015-7-62.Search in Google Scholar PubMed PubMed Central

Gupta, S., Ellis, S.E., Ashar, F.N., Moes, A., Bader, J.S., Zhan, J., West, A.B., and Arking, D.E. (2014). Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat. Commun. 5: 5748, https://doi.org/10.1038/ncomms6748.Search in Google Scholar PubMed PubMed Central

Gustafsson, J.R., Katsioudi, G., Degn, M., Ejlerskov, P., Issaza deh-Navikas, S., and Kornum, B.R. (2018). DNMT1 regulates expression of MHC class I in post-mitotic neurons. Mol. Brain 11: 36, https://doi.org/10.1186/s13041-018-0380-9.Search in Google Scholar PubMed PubMed Central

Hahn, M.A., Jin, S.G., Li, A.X., Liu, J., Huang, Z., Wu, X., Kim, B.W., Johnson, J., Bilbao, A.V., Tao, S., et al.. (2019). Reprogramming of DNA methylation at NEUROD2-bound sequences during cortical neuron differentiation. Sci. Adv. 5: eaax0080. https://doi.org/10.1126/sciadv.aax0080.Search in Google Scholar PubMed PubMed Central

Havránek, T., Lešťanová, Z., Mravec, B., Štrbák, V., Bakoš, J., and Bačová, Z. (2017). Oxytocin modulates expression of neuron and glial markers in the rat Hippocampus. Folia Biol. (Prague) 63: 91–97.Search in Google Scholar

Hu, Z., Xiao, X., Zhang, Z., and Li, M. (2019). Genetic insights and neurobiological implications from NRXN1 in neuropsychiatric disorders. Mol. Psychiatry 24: 1400–1414, https://doi.org/10.1038/s41380-019-0438-9.Search in Google Scholar PubMed

Jaenisch, R. and Bird, A. (2003). Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33: 245–254, https://doi.org/10.1038/ng1089.Search in Google Scholar PubMed

James, S.J., Shpyleva, S., Melnyk, S., Pavliv, O., and Pogribny, I.P. (2014). Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum. Transl. Psychiatry 4: e460, https://doi.org/10.1038/tp.2014.87.Search in Google Scholar PubMed PubMed Central

Jensen, M. and Girirajan, S. (2017). Mapping a shared genetic basis for neurodevelopmental disorders. Genome Med. 9: 109. https://doi.org/10.1186/s13073-017-0503-4.Search in Google Scholar PubMed PubMed Central

Jobe, E.M. and Zhao, X. (2017). DNA methylation and adult neurogenesis. Brain Plast. 3: 5–26, https://doi.org/10.3233/bpl-160034.Search in Google Scholar PubMed PubMed Central

Joensuu, M., Lanoue, V., and Hotulainen, P. (2018). Dendritic spine actin cytoskeleton in autism spectrum disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 84: 362–381, https://doi.org/10.1016/j.pnpbp.2017.08.023.Search in Google Scholar PubMed

Johnstone, K.A., DuBose, A.J., Futtner, C.R., Elmore, M.D., Brannan, C.I., and Resnick, J.L. (2006). A human imprinting centre demonstrates conserved acquisition but diverged maintenance of imprinting in a mouse model for Angelman syndrome imprinting defects. Hum. Mol. Genet. 15: 393–404, https://doi.org/10.1093/hmg/ddi456.Search in Google Scholar PubMed

Kohno, D., Lee, S., Harper, M.J., Kim, K.W., Sone, H., Sasaki, T., Kitamura, T., Fan, G., and Elmquist, J.K. (2014). Dnmt3a in Sim1 neurons is necessary for normal energy homeostasis. J. Neurosci. 34: 15288–15296, https://doi.org/10.1523/jneurosci.1316-14.2014.Search in Google Scholar

Kratsman, N., Getselter, D., and Elliott, E. (2016). Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model. Neuropharmacology 102: 136–145, https://doi.org/10.1016/j.neuropharm.2015.11.003.Search in Google Scholar PubMed

Kubota, T. and Mochizuki, K. (2016). Epigenetic effect of environmental factors on autism spectrum disorders. Int. J. Environ. Res. Public Health 13: 504, https://doi.org/10.3390/ijerph13050504.Search in Google Scholar PubMed PubMed Central

Kumsta, R., Hummel, E., Chen, F.S., and Heinrichs, M. (2013). Epigenetic regulation of the oxytocin receptor gene: implications for behavioral neuroscience. Front. Neurosci. 7: 83, https://doi.org/10.3389/fnins.2013.00083.Search in Google Scholar PubMed PubMed Central

Lee, S., Kozlov, S., Hernandez, L., Chamberlain, S.J., Brannan, C.I., Stewart, C.L., and Wevrick, R. (2000). Expression and imprinting of MAGEL2 suggest a role in Prader-willi syndrome and the homologous murine imprinting phenotype. Hum. Mol. Genet. 9: 1813–1819, https://doi.org/10.1093/hmg/9.12.1813.Search in Google Scholar PubMed

Lesseur, C., Paquette, A.G., and Marsit, C.J. (2014). Epigenetic regulation of infant neurobehavioral outcomes. Med. Epigenet. 2: 71–79, https://doi.org/10.1159/000361026.Search in Google Scholar PubMed PubMed Central

Lewis, M.W., Brant, J.O., Kramer, J.M., Moss, J.I., Yang, T.P., Hansen, P.J., Williams, R.S., and Resnick, J.L. (2015). Angelman syndrome imprinting center encodes a transcriptional promoter. Proc. Natl. Acad. Sci. U.S.A. 112: 6871–6875, https://doi.org/10.1073/pnas.1411261111.Search in Google Scholar PubMed PubMed Central

Li, G., Zhang, W., Baker, M.S., Laritsky, E., Mattan-Hung, N., Yu, D., Kunde-Ramamoorthy, G., Simerly, R.B., Chen, R., Shen, L., et al.. (2014). Major epigenetic development distinguishing neuronal and non-neuronal cells occurs postnatally in the murine hypothalamus. Hum. Mol. Genet. 23: 1579–1590, https://doi.org/10.1093/hmg/ddt548.Search in Google Scholar PubMed PubMed Central

Li, J., Harris, R.A., Cheung, S.W., Coarfa, C., Jeong, M., Goodell, M.A., White, L.D., Patel, A., Kang, S.H., Shaw, C., Chinault, A.C., Gambin, T., Gambin, A., Lupski, J.R., and Milosavljevic, A. (2012). Genomic hypomethylation in the human germline associates with selective structural mutability in the human genome. PLoS Genet. 8: e1002692, https://doi.org/10.1371/journal.pgen.1002692.Search in Google Scholar PubMed PubMed Central

Loke, Y.J., Hannan, A.J., and Craig, J.M. (2015). The role of epigenetic change in autism spectrum disorders. Front. Neurol. 6: 107, https://doi.org/10.3389/fneur.2015.00107.Search in Google Scholar PubMed PubMed Central

Lombardo, M.V., Moon, H.M., Su, J., Palmer, T.D., Courchesne, E., and Pramparo, T. (2018). Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder. Mol. Psychiatry 23: 1001–1013, https://doi.org/10.1038/mp.2017.15.Search in Google Scholar PubMed PubMed Central

Lopatina, O.L., Malinovskaya, N.A., Komleva, Y.K., Gorina, Y.V., Shuvaev, A.N., Olovyannikova, R.Y., Belozor, O.S., Belova, O.A., Higashida, H., and Salmina, A.B. (2019). Excitation/inhibition imbalance and impaired neurogenesis in neurodevelopmental and neurodegenerative disorders. Rev. Neurosci. 30: 807–820, https://doi.org/10.1515/revneuro-2019-0014.Search in Google Scholar PubMed

Lu, X., Yang, B., Yu, H., Hu, X., Nie, J., Wan, B., Zhang, M., and Lü, C. (2019). Epigenetic mechanisms underlying the effects of triptolide and tripchlorolide on the expression of neuroligin-1 in the hippocampus of APP/PS1 transgenic mice. Pharm. Biol. 57: 453–459, https://doi.org/10.1080/13880209.2019.1629463.Search in Google Scholar PubMed PubMed Central

Lux, V. (2018). Epigenetic programming effects of early life stress: a dual-activation hypothesis. Curr. Genom. 19: 638–652, https://doi.org/10.2174/1389202919666180307151358.Search in Google Scholar PubMed PubMed Central

Ma, Q., Xu, Z., Lu, H., Xu, Z., Zhou, Y., Yuan, B., and Ci, W. (2018). Distal regulatory elements identified by methylation and hydroxymethylation haplotype blocks from mouse brain. Epigenet. Chromatin 11: 75, https://doi.org/10.1186/s13072-018-0248-3.Search in Google Scholar PubMed PubMed Central

Matarazzo, V. and Muscatelli, F. (2013). Natural breaking of the maternal silence at the mouse and human imprinted Prader-Willi locus: a whisper with functional consequences. Rare Dis. 1: e27228, https://doi.org/10.4161/rdis.27228.Search in Google Scholar PubMed PubMed Central

Matsuda, K.I., Mori, H., Nugent, B.M., Pfaff, D.W., McCarthy, M.M., and Kawata, M. (2011). Histone deacetylation during brain development is essential for permanent masculinization of sexual behavior. Endocrinology 152: 2760–2767, https://doi.org/10.1210/en.2011-0193.Search in Google Scholar PubMed PubMed Central

Maud, C., Ryan, J., McIntosh, J.E., and Olsson, C.A. (2018). The role of oxytocin receptor gene (OXTR) DNA methylation (DNAm) in human social and emotional functioning: a systematic narrative review. BMC Psychiatry 18: 154, https://doi.org/10.1186/s12888-018-1740-9.Search in Google Scholar PubMed PubMed Central

McCarthy, M.M. (2019). Is sexual differentiation of brain and behavior epigenetic? Curr. Opin. Behav. Sci. 25: 83–88, https://doi.org/10.1016/j.cobeha.2018.10.005.Search in Google Scholar PubMed PubMed Central

McDougle, C.J., Landino, S.M., Vahabzadeh, A., O’Rourke, J., Zurcher, N.R., Finger, B.C., Palumbo, M.L., Helt, J., Mullett, J.E., Hooker, J.M., et al.. (2015). Toward an immune-mediated subtype of autism spectrum disorder. Brain Res. 1617: 72–92, https://doi.org/10.1016/j.brainres.2014.09.048.Search in Google Scholar PubMed

Meaney, M.J. and Szyf, M. (2005). Maternal care as a model for experience-dependent chromatin plasticity? Trends Neurosci. 28: 456–63, https://doi.org/10.1016/j.tins.2005.07.006.Search in Google Scholar PubMed

Mejlachowicz, D., Nolent, F., Maluenda, J., Ranjatoelina-Randrianaivo, H., Giuliano, F., Gut, I., Sternberg, D., Laquerrière, A., and Melki, J. (2015). Truncating mutations of MAGEL2, a gene within the Prader-Willi locus, are responsible for severe arthrogryposis. Am. J. Hum. Genet. 97: 616–620, https://doi.org/10.1016/j.ajhg.2015.08.010.Search in Google Scholar PubMed PubMed Central

Meziane, H., Schaller, F., Bauer, S., Villard, C., Matarazzo, V., Riet, F., Guillon, G., Lafitte, D., Desarmenien, M.G., Tauber, M., et al.. (2014). An early postnatal oxytocin treatment Prevents social and learning deficits in adult mice deficient for Magel2, a gene involved in Prader-Willi syndrome and autism. Biol. Psychiatry 78: 85–94, https://doi.org/10.1016/j.biopsych.2014.11.010.Search in Google Scholar PubMed

Montenegro, Y.H.A., de Queiroga Nascimento, D., de Assis, T.O., and Santos-Lopes, S.S.D. (2019). The epigenetics of the hypothalamic-pituitary-adrenal axis in fetal development. Ann. Hum. Genet. 83: 195–213, https://doi.org/10.1111/ahg.12306.Search in Google Scholar PubMed

Mosley, M., Weathington, J., Cortes, L.R., Bruggeman, E., Castillo-Ruiz, A., Xue, B., and Forger, N.G. (2017). Neonatal inhibition of DNA methylation alters cell phenotype in sexually dimorphic regions of the mouse brain. Endocrinology 158: 1838–1848, https://doi.org/10.1210/en.2017-00205.Search in Google Scholar PubMed PubMed Central

Murgatroyd, C. (2020). Epigenetic modifications of early-life stress and adult life psychopathology. In: Teixeira, A., Macedo, D., and Baune, B. (Eds.), Perinatal inflammation and adult psychopathology. Berlin: Springer, pp. 33–48.10.1007/978-3-030-39335-9_3Search in Google Scholar

Nagarajan, R.P., Hogart, A.R., Gwye, Y., Martin, M.R., and LaSalle, J.M. (2006). Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics 1: e1–e11, https://doi.org/10.4161/epi.1.4.3514.Search in Google Scholar PubMed PubMed Central

Nagarajan, R.P., Patzel, K.A., Martin, M., Yasui, D.H., Swanberg, S.E., Hertz-Picciotto, I., Hansen, R.L., Van de Water, J., Pessah, I.N., Jiang, R., et al.. (2008). MECP2 promoter methylation and X chromosome inactivation in autism. Autism Res. 1: 169–178, https://doi.org/10.1002/aur.24.Search in Google Scholar PubMed PubMed Central

Nardone, S. and Elliott, E. (2016). The interaction between the immune system and epigenetics in the etiology of autism spectrum disorders. Front. Neurosci. 10: 329, https://doi.org/10.3389/fnins.2016.00329.Search in Google Scholar PubMed PubMed Central

Noguchi, H., Kimura, A., Murao, N., Matsuda, T., Namihira, M., and Nakashima, K. (2015). Expression of DNMT1 in neural stem/precursor cells is critical for survival of newly generated neurons in the adult hippocampus. Neurosci. Res. 95: 1–11, https://doi.org/10.1016/j.neures.2015.01.014.Search in Google Scholar PubMed

Nowialis, P., Lopusna, K., Opavska, J., Haney, S.L., Abraham, A., Sheng, P., Riva, A., Natarajan, A., Guryanova, O., Simpson, M., et al.. (2019). Catalytically inactive Dnmt3b rescues mouse embryonic development by accessory and repressive functions. Nat. Commun. 10: 4374, https://doi.org/10.1038/s41467-019-12355-7.Search in Google Scholar PubMed PubMed Central

Nugent, B.M., Wright, C.L., Shetty, A.C., Hodes, G.E., Lenz, K.M., Mahurkar, A., Russo, S.J., Devine, S.E., and McCarthy, M.M. (2015). Brain feminization requires active repression of masculinization via DNA methylation. Nat. Neurosci. 18: 690–697, https://doi.org/10.1038/nn.3988.Search in Google Scholar PubMed PubMed Central

Obri, A. and Claret, M. (2019). The role of epigenetics in hypothalamic energy balance control: implications for obesity. Cell Stress 3: 208–220, https://doi.org/10.15698/cst2019.07.191.Search in Google Scholar PubMed PubMed Central

Oh, J.E., Chambwe, N., Klein, S., Gal, J., Andrews, S., Gleason, G., Shaknovich, R., Melnick, A., Campagne, F., and Toth, M. (2013). Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment. Transl. Psychiatry 3: e218, https://doi.org/10.1038/tp.2012.130.Search in Google Scholar PubMed PubMed Central

Pelling, M., Anthwal, N., McNay, D., Gradwohl, G., Leiter, A.B., Guillemot, F., and Ang, S.L. (2011). Differential requirements for neurogenin 3 in the development of POMC and NPY neurons in the hypothalamus. Dev. Biol. 349: 406–416, https://doi.org/10.1016/j.ydbio.2010.11.007.Search in Google Scholar PubMed

Pfeifer, K. (2000). Mechanism of genomic imprinting. Am. J. Hum. Genet. 67: 777–787, https://doi.org/10.1086/303101.Search in Google Scholar PubMed PubMed Central

Provenzi, L., Brambilla, M., Scotto di Minico, G., Montirosso, R., and Borgatti, R. (2020). Maternal caregiving and DNA methylation in human infants and children: systematic review. Gene Brain Behav. 19: e12616. https://doi.org/10.1111/gbb.12616.Search in Google Scholar PubMed

Ratnu, V.S., Emami, M.R., and Bredy, T.W. (2017). Genetic and epigenetic factors underlying sex differences in the regulation of gene expression in the brain. J. Neurosci. Res. 95: 301–310, https://doi.org/10.1002/jnr.23886.Search in Google Scholar PubMed PubMed Central

Reichova, A., Bacova, Z., Bukatova, S., Kokavcova, M., Meliskova, V., Frimmel, K., Ostatnikova, D., and Bakos, J. (2020). Abnormal neuronal morphology and altered synaptic proteins are restored by oxytocin in autism-related SHANK3 deficient model. Mol. Cell. Endocrinol. 518: 110924, https://doi.org/10.1016/j.mce.2020.110924.Search in Google Scholar PubMed

Reichova, A., Schaller, F., Bukatova, S., Bacova, Z., Muscatelli, F., and Bakos, J. (2021). The impact of oxytocin on neurite outgrowth and synaptic proteins in Magel2-deficient mice. Dev Neurobiol 81: 366–388. https://doi.org/10.1002/dneu.22815.Search in Google Scholar PubMed

Resnick, J.L., Nicholls, R.D., and Wevrick, R. (2013). Prader-Willi syndrome animal models Working group. Recommendations for the investigation of animal models of Prader-Willi syndrome. Mamm. Genome 24: 165–178, https://doi.org/10.1007/s00335-013-9454-2.Search in Google Scholar PubMed

Ruiz-Palmero, I., Ortiz-Rodriguez, A., Melcangi, R.C., Caruso, D., Garcia-Segura, L.M., Rune, G.M., and Arevalo, M.A. (2016). Oestradiol synthesized by female neurons generates sex differences in neuritogenesis. Sci. Rep. 6: 31891, https://doi.org/10.1038/srep31891.Search in Google Scholar PubMed PubMed Central

Salminen, I., Read, S., Hurd, P., and Crespi, B. (2020). Does SNORD116 mediate aspects of psychosis in Prader-Willi syndrome? Evidence from a non-clinical population. Psychiatry Res. 286: 112858, https://doi.org/10.1016/j.psychres.2020.112858.Search in Google Scholar PubMed

Santiago, M., Antunes, C., Guedes, M., Sousa, N., and Marques, C.J. (2014). TET enzymes and DNA hydroxymethylation in neural development and function - how critical are they? Genomics 104: 334–340, doi:10.1016/j.ygeno.2014.08.018.10.1016/j.ygeno.2014.08.018Search in Google Scholar PubMed

Scerbo, M.J., Freire-Regatillo, A., Cisternas, C.D., Brunotto, M., Arevalo, M.A., Garcia-Segura, L.M., and Cambiasso, M.J. (2014). Neurogenin 3 mediates sex chromosome effects on the generation of sex differences in hypothalamic neuronal development. Front. Cell. Neurosci. 8: 188, https://doi.org/10.3389/fncel.2014.00188.Search in Google Scholar PubMed PubMed Central

Schaaf, R.C., Benevides, T., Mailloux, Z., Faller, P., Hunt, J., van Hooydonk, E., Freeman, R., Leiby, B., Sendecki, J., and Kelly, D. (2014). An intervention for sensory difficulties in children with autism: a randomized trial. J. Autism Dev. Disord. 44: 1493–1506, https://doi.org/10.1007/s10803-014-2111-0.Search in Google Scholar PubMed

Sendžikaitė, G., Hanna, C.W., Stewart-Morgan, K.R., Ivanova, E., and Kelsey, G. (2019). A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice. Nat. Commun. 10: 1884, https://doi.org/10.1038/s41467-019-09713-w.Search in Google Scholar PubMed PubMed Central

Simmons, R.K., Howard, J.L., Simpson, D.N., Akil, H., and Clinton, S.M. (2012). DNA methylation in the developing hippocampus and amygdala of anxiety-prone versus risk-taking rats. Dev. Neurosci. 34: 58–67, https://doi.org/10.1159/000336641.Search in Google Scholar PubMed PubMed Central

Sohal, V.S. and Rubenstein, J.L.R. (2019). Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders. Mol. Psychiatry 24: 1248–1257, https://doi.org/10.1038/s41380-019-0426-0.Search in Google Scholar

Swaab, D.F., Chung, W.C., Kruijver, F.P., Hofman, M.A., and Hestiantoro, A. (2003). Sex differences in the hypothalamus in the different stages of human life. Neurobiol. Aging 24: S1–S16, discussion S17–S19, https://doi.org/10.1016/s0197-4580(03)00059-9.Search in Google Scholar

Symmank, J. and Zimmer, G. (2017). Regulation of neuronal survival by DNA methyltransferases. Neural. Regen. Res. 12: 1768–1775, https://doi.org/10.4103/1673-5374.219027.Search in Google Scholar PubMed PubMed Central

Tacer, K.F. and Potts, P.R. (2017). Cellular and disease functions of the Prader-Willi Syndrome gene MAGEL2. Biochem. J. 474: 2177–2190, https://doi.org/10.1042/bcj20160616.Search in Google Scholar PubMed PubMed Central

Tremblay, M.W. and Jiang, Y.-H. (2019). DNA methylation and susceptibility to autism spectrum disorder. Annu. Rev. Med. 70: 151–166, https://doi.org/10.1146/annurev-med-120417-091431.Search in Google Scholar PubMed PubMed Central

Vahabzadeh, A. and McDougle, C.J. (2013). Maternal folic acid supplementation and risk of autism. J. Am. Med. Assoc. 309: 2208, https://doi.org/10.1001/jama.2013.4876.Search in Google Scholar PubMed

Vargas, D.L., Nascimbene, C., Krishnan, C., Zimmerman, A.W., and Pardo, C.A. (2005). Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 57: 67–81, https://doi.org/10.1002/ana.20315.Search in Google Scholar PubMed

Vogel-Ciernia, A., Laufer, B.I., Dunaway, K.W., Mordaunt, C.E., Coulson, R.L., Totah, T.S., Stolzenberg, D.S., Frahm, J.C., Singh-Taylor, A., Baram, T.Z., et al.. (2018). Experience-dependent neuroplasticity of the developing hypothalamus: integrative epigenomic approaches. Epigenetics 13: 318–330, https://doi.org/10.1080/15592294.2018.1451720.Search in Google Scholar PubMed PubMed Central

Walker, D.M., Kirson, D., Perez, L.F., and Gore, A.C. (2012). Molecular profiling of postnatal development of the hypothalamus in female and male rats. Biol. Reprod. 87: 129, https://doi.org/10.1095/biolreprod.112.102798.Search in Google Scholar PubMed PubMed Central

Wang, C.R., Sun, Y.H., and Xu, T. (2020). [Cohort studies on the association between maternal smoking during pregnancy and autism spectrum disorders of children: a meta-analysis]. Zhonghua liu xing bing xue za zhi 41: 1921–1926, https://doi.org/10.3760/cma.j.cn112338-20191009-00722.Search in Google Scholar PubMed

Wei, H., Liang, F., Meng, G., Nie, Z., Zhou, R., Cheng, W., Wu, X., Feng, Y., and Wang, Y. (2016). Redox/methylation mediated abnormal DNA methylation as regulators of ambient fine particulate matter-induced neurodevelopment related impairment in human neuronal cells. Sci. Rep. 6: 33402, https://doi.org/10.1038/srep33402.Search in Google Scholar PubMed PubMed Central

Weiner, D.J., Wigdor, E.M., Ripke, S., Walters, R.K., Kosmicki, J.A., Grove, J., Samocha, K.E., Goldstein, J.I., Okbay, A., Bybjerg-Grauholm, J., et al.. (2017). Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. Nat. Genet. 49: 978–985, https://doi.org/10.1038/ng.3863.Search in Google Scholar PubMed PubMed Central

Wong, C.C.Y., Smith, R.G., Hannon, E., Ramaswami, G., Parikshak, N.N., Assary, E., Troakes, C., Poschmann, J., Schalkwyk, L.C., Sun, W., et al.. (2019). Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue. Hum. Mol. Genet. 28: 2201–2211, https://doi.org/10.1093/hmg/ddz052.Search in Google Scholar PubMed PubMed Central

Wu, X. and Zhang, Y. (2017). TET-mediated active DNA demethylation: mechanism, function and beyond. Nat. Rev. Genet. 18: 517–34, https://doi.org/10.1038/nrg.2017.33.Search in Google Scholar PubMed

Yoon, S.H., Choi, J., Lee, W.J., and Do, J.T. (2020). Genetic and epigenetic etiology underlying autism spectrum disorder. J. Clin. Med. 9: 966, https://doi.org/10.3390/jcm9040966.Search in Google Scholar PubMed PubMed Central

Yuan, X., Zhou, X., Chen, Z., He, Y., Kong, Y., Ye, S., Gao, N., Zhang, Z., Zhang, H., and Li, J. (2019). Genome-wide DNA methylation analysis of hypothalamus during the onset of puberty in gilts. Front. Genet. 10: 228, https://doi.org/10.3389/fgene.2019.00228.Search in Google Scholar PubMed PubMed Central

Zerbo, O., Qian, Y., Yoshida, C., Grether, J.K., Van de Water, J., and Croen, L.A. (2015). Maternal infection during pregnancy and autism spectrum disorders. J. Autism Dev. Disord. 45: 4015–4025, https://doi.org/10.1007/s10803-013-2016-3.Search in Google Scholar PubMed PubMed Central

Zhu, L., Wang, X., Li, X.L., Towers, A., Cao, X., Wang, P., Bowman, R., Yang, H., Goldstein, J., Li, Y.J., et al.. (2014). Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders. Hum. Mol. Genet. 23: 1563–1578, https://doi.org/10.1093/hmg/ddt547.Search in Google Scholar PubMed PubMed Central

Zhu, Y., Mordaunt, C.E., Yasui, D.H., Marathe, R., Coulson, R.L., Dunaway, K.W., Jianu, J.M., Walker, C.K., Ozonoff, S., Hertz-Picciotto, I., et al.. (2019). Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study. Hum. Mol. Genet. 28: 2659–2674, https://doi.org/10.1093/hmg/ddz084.Search in Google Scholar PubMed PubMed Central

Zhubi, A., Chen, Y., Guidotti, A., and Grayson, D.R. (2017). Epigenetic regulation of RELN and GAD1 in the frontal cortex (FC) of autism spectrum disorder (ASD) subjects. Int. J. Dev. Neurosci. 62: 63–72, https://doi.org/10.1016/j.ijdevneu.2017.02.003.Search in Google Scholar PubMed PubMed Central

Received: 2021-01-26
Accepted: 2021-04-12
Published Online: 2021-05-04
Published in Print: 2021-11-25

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 23.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/revneuro-2021-0014/html?lang=en
Scroll to top button