Division of Molecular Biology, Ruđer Bošković Institute, 10000, Zagreb, Croatia.
Department of Biology, Faculty of Science, University of Zagreb, 10000, Zagreb, Croatia.
Clin Epigenetics. 2024 Jan 3;16(1):4. doi: 10.1186/s13148-023-01610-w.
Serotonin (5-hydroxytryptamine, 5-HT) signaling is involved in neurodevelopment, mood regulation, energy metabolism, and other physiological processes. DNA methylation plays a significant role in modulating the expression of genes responsible for maintaining 5-HT balance, such as 5-HT transporter (SLC6A4), monoamine oxidase A (MAOA), and 5-HT receptor type 2A (HTR2A). Maternal metabolic health can influence long-term outcomes in offspring, with DNA methylation mediating these effects. We investigated associations between maternal metabolic parameters-pre-pregnancy body mass index (pBMI), gestational weight gain (GWG), and glucose tolerance status (GTS), i.e., gestational diabetes mellitus (GDM) versus normal glucose tolerance (NGT)-and cord blood methylation of SLC6A4, MAOA, and HTR2A in participants from our PlaNS birth cohort. CpG sites (15, 9, and 2 in each gene, respectively) were selected based on literature and in silico data. Methylation levels were quantified by bisulfite pyrosequencing. We also examined the stability of methylation patterns in these genes in circulating blood cells from birth to adolescence using longitudinal DNA methylation data from the ARIES database.
None of the 203 PlaNS mothers included in this study had preexisting diabetes, 99 were diagnosed with GDM, and 104 had NGT; all neonates were born at full term by planned Cesarean section. Methylation at most CpG sites differed between male and female newborns. SLC6A4 methylation correlated inversely with maternal pBMI and GWG, while methylation at HTR2A site -1665 correlated positively with GWG. None of the maternal metabolic parameters statistically associated with MAOA methylation. DNA methylation data in cord blood and peripheral blood at ages 7 and 15 years were available for 808 participants from the ARIES database; 4 CpG sites (2 in SLC6A4 and 2 in HTR2A) overlapped between the PlaNS and ARIES cohorts. A positive correlation between methylation levels in cord blood and peripheral blood at 7 and 15 years of age was observed for both SLC6A4 and HTR2A CpG sites.
Methylation of 5-HT regulating genes in cord blood cells is influenced by neonatal sex, with maternal metabolism playing an additional role. Inter-individual variations present in circulating blood cells at birth are still pronounced in childhood and adolescence.
血清素（5-羟色胺，5-HT）信号参与神经发育、情绪调节、能量代谢和其他生理过程。DNA 甲基化在调节负责维持 5-HT 平衡的基因表达方面起着重要作用，如 5-HT 转运体（SLC6A4）、单胺氧化酶 A（MAOA）和 5-HT 受体 2A（HTR2A）。母体代谢健康会影响后代的长期结局，而 DNA 甲基化介导了这些影响。我们研究了母体代谢参数-孕前体重指数（pBMI）、妊娠体重增加（GWG）和葡萄糖耐量状态（GTS），即妊娠期糖尿病（GDM）与正常葡萄糖耐量（NGT）-与 PlAnS 出生队列参与者脐带血中 SLC6A4、MAOA 和 HTR2A 甲基化之间的关系。根据文献和计算机数据选择了 15、9 和 2 个基因中的每个基因的 CpG 位点。通过亚硫酸氢盐焦磷酸测序定量甲基化水平。我们还使用 ARIES 数据库中的纵向 DNA 甲基化数据，检查了这些基因在出生到青春期循环血细胞中甲基化模式的稳定性。
本研究纳入的 203 名 PlAnS 母亲中均无糖尿病前期，99 名被诊断为 GDM，104 名为 NGT；所有新生儿均通过计划剖宫产足月分娩。大多数 CpG 位点的甲基化在男婴和女婴之间存在差异。SLC6A4 甲基化与母体 pBMI 和 GWG 呈负相关，而 HTR2A 位点-1665 与 GWG 呈正相关。母体代谢参数与 MAOA 甲基化无统计学相关性。ARIES 数据库中 808 名参与者可提供脐带血和 7 岁和 15 岁外周血的 DNA 甲基化数据；PlAnS 和 ARIES 队列中有 4 个 CpG 位点（SLC6A4 中的 2 个和 HTR2A 中的 2 个）重叠。在 7 岁和 15 岁时，脐带血和外周血中 SLC6A4 和 HTR2A CpG 位点的甲基化水平呈正相关。
脐带血细胞中 5-HT 调节基因的甲基化受新生儿性别影响，母体代谢起额外作用。出生时循环血细胞中的个体间差异在儿童和青少年时期仍很明显。
