Data_Sheet_2_Anticonvulsants and Chromatin-Genes Expression: A Systems Biology Investigation.pdf

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’ 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 SMARCA2 and SMARCA4, and nine genes to Fetal Hydantoin Syndrome, including PAX6, NEUROD1, and TSHZ1. 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.

胚胎胎儿的发育过程至关重要，需严格受表观遗传学的调控，然而，这一平衡的扰动可能导致先天性畸形的产生。众所周知，抗惊厥药物可能影响与表观遗传学相关的基因，然而，尚不清楚这种不平衡是否可以解释抗惊厥药物引起的胎儿综合征。在本研究中，我们旨在评估在丙戊酸、卡马西平或苯妥英暴露下与表观遗传学相关的基因的表达。我们选择了这三种抗惊厥药物暴露检测方法，这些方法使用了小鼠或人胚胎干细胞，并在基因组数据库中公开发布。我们进行了差异基因表达（DGE）和加权基因共表达网络分析（WGCNA），重点关注与表观遗传学相关的基因。在抗惊厥药物的暴露中，仅有少数表观遗传学基因表现出差异表达，然而，WGCNA策略显示出三种药物在染色质重塑基因上的高富集。我们还鉴定出与胎儿丙戊酸综合征相关的46个基因，包括SMARCA2和SMARCA4，以及与胎儿苯妥英综合征相关的9个基因，包括PAX6、NEUROD1和TSHZ1。对药物暴露下的干细胞的评估可为理解药物对胚胎胎儿发育的诱导性损伤提供诸多洞见。此处提出的候选基因是潜在的生物标志物，有助于未来预防先天性畸形的预防策略。