Mother and Child Health, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be) University, Pune 411043, India.
Genomic Research on Complex diseases (GRC Group), CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad 500007. India.
Prostaglandins Leukot Essent Fatty Acids. 2022 Sep;184:102472. doi: 10.1016/j.plefa.2022.102472. Epub 2022 Jul 6.
Biosynthesis of long-chain polyunsaturated fatty acids requires sequential activities of desaturases and elongases for conversion of fatty acid precursors to products. The delta-6 desaturase enzyme, encoded by FADS2 gene, is a rate limiting enzyme in this pathway. Alterations in D6D enzyme activity can lead to altered fatty acid profiles.
To examine differences in placental DNA methylation (DNAm) and expression of FADS2 gene in preeclampsia women compared to normal women and their association with maternal variables (plasma fatty acids, desaturase enzyme index, blood pressure), placental weight and birth outcomes.
DNAm and expression of FADS2 gene were examined in placentae of normotensive (n = 100) control and preeclampsia (n = 100) women using pyrosequencing and quantitative real-time PCR respectively. Women with preeclampsia included those delivering at term (n = 43, gestation ≥ 37 weeks; T-PE) or preterm (n = 57, gestation < 37 weeks; PT-PE). A total of 26 CpGs in FADS2 promoter and region around it, were analysed in two PCR reactions (region 1 and 2).
Out of 13 CpGs in region 1, significant hypermethylation was noted at CpG3 in T-PE (p = 0.03) and of 13 CpGs in region 2, CpG2 (p = 0.008), CpG11 (p = 0.04), CpG12 (p = 0.001) were hypomethylated and CpG13 (p = 0.001) was hypermethylated in preeclampsia group, as compared to controls. FADS2 expression was lower in PT-PE as compared to controls (p = 0.04). DNAm at various CpGs in the FADS2 were associated with maternal plasma FADS2 enzyme index and also associated with maternal fatty acid levels. However, we did not observe any association of DNAm with maternal blood pressure, placental weight and birth outcomes.
This study for the first time reports differential methylation of FADS2 and its association with impaired maternal fatty acid metabolism in preeclampsia and provides a mechanistic basis to our earlier observations of altered maternal LCPUFA levels in women with preeclampsia.
长链多不饱和脂肪酸的生物合成需要去饱和酶和延伸酶的连续活性，将脂肪酸前体转化为产物。Delta-6 去饱和酶，由 FADS2 基因编码，是该途径中的限速酶。D6D 酶活性的改变可导致脂肪酸谱的改变。
检测子痫前期妇女胎盘 DNA 甲基化（DNAm）和 FADS2 基因表达与正常妇女的差异，并与母体变量（血浆脂肪酸、去饱和酶指数、血压）、胎盘重量和出生结局相关。
采用焦磷酸测序和实时定量 PCR 分别检测 100 例正常对照和 100 例子痫前期妇女胎盘的 FADS2 基因 DNAm 和表达。子痫前期患者包括足月（n=43，妊娠≥37 周；T-PE）或早产（n=57，妊娠<37 周；PT-PE）。在两个 PCR 反应（区域 1 和 2）中分析了 FADS2 启动子及其周围的 26 个 CpG。
在区域 1 的 13 个 CpG 中，T-PE 中 CpG3 出现显著的高甲基化（p=0.03），在区域 2 的 13 个 CpG 中，CpG2（p=0.008）、CpG11（p=0.04）、CpG12（p=0.001）呈低甲基化，CpG13（p=0.001）呈高甲基化。与对照组相比，子痫前期组 FADS2 表达降低（p=0.04）。FADS2 基因在不同 CpG 位点的 DNAm 与母体血浆 FADS2 酶指数相关，也与母体脂肪酸水平相关。然而，我们没有观察到 DNAm 与母体血压、胎盘重量和出生结局之间的任何关联。
本研究首次报道了 FADS2 的差异甲基化及其与子痫前期中母体脂肪酸代谢受损的关联，并为我们之前观察到子痫前期妇女母体 LCPUFA 水平改变提供了机制基础。
