{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T09:02:18Z","timestamp":1777626138492,"version":"3.51.4"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T00:00:00Z","timestamp":1606262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["88881.132344\/2016-01"],"award-info":[{"award-number":["88881.132344\/2016-01"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["573993\/2008-4"],"award-info":[{"award-number":["573993\/2008-4"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["465549\/2014-4"],"award-info":[{"award-number":["465549\/2014-4"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["312993\/2017-0"],"award-info":[{"award-number":["312993\/2017-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["156158\/2018-3"],"award-info":[{"award-number":["156158\/2018-3"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004263","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio Grande do Sul","doi-asserted-by":"publisher","award":["17\/2551.0000521-0"],"award-info":[{"award-number":["17\/2551.0000521-0"]}],"id":[{"id":"10.13039\/501100004263","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Embryofetal development is a critical process that needs a strict epigenetic control, however, perturbations in this balance might lead to the occurrence of congenital anomalies. It is known that anticonvulsants potentially affect epigenetics-related genes, however, it is not comprehended whether this unbalance could explain the anticonvulsants-induced fetal syndromes. In the present study, we aimed to evaluate the expression of epigenetics-related genes in valproic acid, carbamazepine, or phenytoin exposure. We selected these three anticonvulsants exposure assays, which used murine or human embryonic stem-cells and were publicly available in genomic databases. We performed a differential gene expression (DGE) and weighted gene co-expression network analysis (WGCNA), focusing on epigenetics-related genes. Few epigenetics genes were differentially expressed in the anticonvulsants\u2019 exposure, however, the WGCNA strategy demonstrated a high enrichment of chromatin remodeling genes for the three drugs. We also identified an association of 46 genes related to Fetal Valproate Syndrome, containing <jats:italic>SMARCA2<\/jats:italic> and <jats:italic>SMARCA4<\/jats:italic>, and nine genes to Fetal Hydantoin Syndrome, including <jats:italic>PAX6, NEUROD1<\/jats:italic>, and <jats:italic>TSHZ1<\/jats:italic>. The evaluation of stem-cells under drug exposure can bring many insights to understand the drug-induced damage to the embryofetal development. The candidate genes here presented are potential biomarkers that could help in future strategies for the prevention of congenital anomalies.<\/jats:p>","DOI":"10.3389\/fnins.2020.591196","type":"journal-article","created":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T06:34:39Z","timestamp":1606286079000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Anticonvulsants and Chromatin-Genes Expression: A Systems Biology Investigation"],"prefix":"10.3389","volume":"14","author":[{"given":"Thayne Woycinck","family":"Kowalski","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia do Amaral","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maril\u00e9a Furtado","family":"Feira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1gata de Vargas","family":"Dupont","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana","family":"Recamonde-Mendoza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernanda Sales Luiz","family":"Vianna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2020,11,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/genes8060150","article-title":"Maternal factors that induce epigenetic changes contribute to neurological disorders in offspring.","volume":"8","author":"Banik","year":"2017","journal-title":"Genes"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1101\/gr.190629.115","article-title":"The Mendelian disorders of the epigenetic machinery.","volume":"25","author":"Bjornsson","year":"2015","journal-title":"Genome Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.ejmg.2016.09.011","article-title":"Human teratogens and genetic phenocopies. Understanding pathogenesis through human genes mutation.","volume":"60","author":"Cassina","year":"2017","journal-title":"Eur. J. Med. Genet."},{"key":"B4","doi-asserted-by":"crossref","DOI":"10.1186\/s13072-019-0254-0","article-title":"Preconception paternal alcohol exposure exerts sex-specific effects on offspring growth and long-term metabolic programming.","volume":"12","author":"Chang","year":"2019","journal-title":"Epigenet. Chromatin"},{"key":"B5","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1146\/annurev.biochem.77.062706.153223","article-title":"The biology of chromatin remodeling complexes.","volume":"78","author":"Clapier","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"5043","DOI":"10.2174\/1381612811319280003","article-title":"Histone acetylation in neurodevelopment.","volume":"19","author":"Contestabile","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"B7","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ejogrb.2004.04.022","article-title":"Risk of drug-induced congenital defects.","volume":"117","author":"De Santis","year":"2004","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"B8","first-page":"99","article-title":"Teratogenic causes of malformations.","volume":"40","author":"Gilbert-Barness","year":"2010","journal-title":"Ann. Clin. Lab. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1594","DOI":"10.1111\/acer.13135","article-title":"An update on fetal alcohol syndrome-pathogenesis, risks, and treatment.","volume":"40","author":"Gupta","year":"2016","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1124\/pr.119.017681","article-title":"Druggable transcriptional networks in the human neurogenic epigenome.","volume":"71","author":"Higgins","year":"2019","journal-title":"Pharmacol. Rev."},{"key":"B11","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1093\/bfgp\/eln027","article-title":"Systems biology at the Institute for systems biology.","volume":"7","author":"Hood","year":"2008","journal-title":"Brief Funct. Genomic Proteomic"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci10080545","article-title":"Differential expression of multiple disease-related protein groups induced by valproic acid in human SH-SY5Y neuroblastoma cells.","volume":"10","author":"Hu","year":"2020","journal-title":"Brain Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1038\/s41580-019-0151-1","article-title":"Roles and regulation of histone methylation in animal development.","volume":"20","author":"Jambhekar","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.reprotox.2019.07.015","article-title":"Assembling systems biology, embryo development and teratogenesis: what do we know so far and where to go next?","volume":"88","author":"Kowalski","year":"2019","journal-title":"Reprod. Toxicol."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis.","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1038\/nrg3885","article-title":"Quantitative and logic modelling of molecular and gene networks.","volume":"16","author":"Le Nov\u00e8re","year":"2015","journal-title":"Nat. Rev. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1007\/s00204-019-02632-1","article-title":"A novel dual reporter embryonic stem cell line for toxicological assessment of teratogen-induced perturbation of anterior-posterior patterning of the heart.","volume":"94","author":"Leigh","year":"2020","journal-title":"Arch. Toxicol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1136\/jmg.2009.070466","article-title":"Can our understanding of epigenetics assist with primary prevention of congenital defects?","volume":"47","author":"Mart\u00ednez-Fr\u00edas","year":"2010","journal-title":"J. Med. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1111\/j.1365-2125.2009.03544.x","article-title":"Exposure to folic acid antagonists during the first trimester of pregnancy and the risk of major malformations.","volume":"68","author":"Matok","year":"2009","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1590\/1678-4685-gmb-2016-0179","article-title":"Teratogens: a public health issue - a Brazilian overview.","volume":"40","author":"Mazzu-Nascimento","year":"2017","journal-title":"Genet. Mol. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1093\/carcin\/bgl167","article-title":"Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes.","volume":"28","author":"Milutinovic","year":"2007","journal-title":"Carcinogenesis"},{"key":"B22","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ajog.2011.02.029","article-title":"Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008.","volume":"205","author":"Mitchell","year":"2011","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.tibs.2014.04.003","article-title":"PRDM14: a unique regulator for pluripotency and epigenetic reprogramming.","volume":"39","author":"Nakaki","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.expneurol.2017.04.017","article-title":"The valproic acid-induced rodent model of autism.","volume":"299","author":"Nicolini","year":"2018","journal-title":"Exp. Neurol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.reprotox.2006.03.014","article-title":"Neuroteratogens in man: an overview with special emphasis on the teratogenicity of antiepileptic drugs in pregnancy.","volume":"22","author":"Ornoy","year":"2006","journal-title":"Reprod. Toxicol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1101\/sqb.2016.81.031021","article-title":"Composition and Function of Mammalian SWI\/SNF Chromatin Remodeling Complexes in Human Disease.","volume":"81","author":"Pulice","year":"2016","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.83","article-title":"Ubiquitylation at the crossroads of development and disease.","volume":"19","author":"Rape","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.anireprosci.2014.05.015","article-title":"Embryo transcriptome response to environmental factors: implication for its survival under suboptimal conditions.","volume":"149","author":"Salilew-Wondim","year":"2014","journal-title":"Anim. Reprod. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1093\/toxsci\/kfv094","article-title":"Gene expression regulation and pathway analysis after valproic acid and carbamazepine exposure in a human embryonic stem cell-based neurodevelopmental toxicity assay.","volume":"146","author":"Schulpen","year":"2015","journal-title":"Toxicol. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1038\/s41556-018-0144-x","article-title":"Deconstructing and reconstructing the mouse and human early embryo.","volume":"20","author":"Shahbazi","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1093\/toxsci\/kfs333","article-title":"Complementary detection of embryotoxic properties of substances in the neural and cardiac embryonic stem cell tests.","volume":"132","author":"Theunissen","year":"2013","journal-title":"Toxicol. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.taap.2012.05.011","article-title":"Compound-specific effects of diverse neurodevelopmental toxicants on global gene expression in the neural embryonic stem cell test (ESTn).","volume":"262","author":"Theunissen","year":"2012","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1097\/wco.0000000000000659","article-title":"Teratogenicity of antiepileptic drugs.","volume":"32","author":"Tomson","year":"2019","journal-title":"Curr. Opin. Neurol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.taap.2010.08.001","article-title":"Epigenetic modifications in valproic acid-induced teratogenesis.","volume":"248","author":"Tung","year":"2010","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1093\/toxsci\/kfq291","article-title":"Evaluation of developmental toxicant identification using gene expression profiling in embryonic stem cell differentiation cultures.","volume":"119","author":"van Dartel","year":"2011","journal-title":"Toxicol. Sci."},{"key":"B36","doi-asserted-by":"crossref","first-page":"D433","DOI":"10.1093\/nar\/gki005","article-title":"STRING: known and predicted protein-protein associations, integrated and transferred across organisms.","volume":"33","author":"von Mering","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1038\/nature13045","article-title":"ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression.","volume":"10","author":"Wen","year":"2014","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1039\/c8ib00082d","article-title":"Teratogen screening with human pluripotent stem cells.","volume":"10","author":"Worley","year":"2018","journal-title":"Integr. Biol."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2020.591196\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T06:34:43Z","timestamp":1606286083000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2020.591196\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,25]]},"references-count":38,"alternative-id":["10.3389\/fnins.2020.591196"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2020.591196","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,25]]},"article-number":"591196"}}