Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
Department of Pediatrics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
Clin Epigenetics. 2024 Aug 13;16(1):104. doi: 10.1186/s13148-024-01718-7.
The plasma metabolome reflects the physiological state of various biological processes and can serve as a proxy for disease risk. Plasma metabolite variation, influenced by genetic and epigenetic mechanisms, can also affect the cellular microenvironment and blood cell epigenetics. The interplay between the plasma metabolome and the blood cell epigenome remains elusive. In this study, we performed an epigenome-wide association study (EWAS) of 1183 plasma metabolites in 693 participants from the LifeLines-DEEP cohort and investigated the causal relationships in DNA methylation-metabolite associations using bidirectional Mendelian randomization and mediation analysis.
After rigorously adjusting for potential confounders, including genetics, we identified five robust associations between two plasma metabolites (L-serine and glycine) and three CpG sites located in two independent genomic regions (cg14476101 and cg16246545 in PHGDH and cg02711608 in SLC1A5) at a false discovery rate of less than 0.05. Further analysis revealed a complex bidirectional relationship between plasma glycine/serine levels and DNA methylation. Moreover, we observed a strong mediating role of DNA methylation in the effect of glycine/serine on the expression of their metabolism/transport genes, with the proportion of the mediated effect ranging from 11.8 to 54.3%. This result was also replicated in an independent population-based cohort, the Rotterdam Study. To validate our findings, we conducted in vitro cell studies which confirmed the mediating role of DNA methylation in the regulation of PHGDH gene expression.
Our findings reveal a potential feedback mechanism in which glycine and serine regulate gene expression through DNA methylation.
血浆代谢组反映了各种生物过程的生理状态，可以作为疾病风险的替代物。受遗传和表观遗传机制影响的血浆代谢物变化也会影响细胞微环境和血细胞表观遗传学。血浆代谢组与血细胞表观基因组之间的相互作用仍然难以捉摸。在这项研究中，我们对来自 LifeLines-DEEP 队列的 693 名参与者的 1183 种血浆代谢物进行了全基因组关联研究（EWAS），并使用双向孟德尔随机化和中介分析研究了 DNA 甲基化-代谢物关联中的因果关系。
在严格调整包括遗传在内的潜在混杂因素后，我们确定了两种血浆代谢物（L-丝氨酸和甘氨酸）和三个 CpG 位点之间的五个稳健关联，这三个 CpG 位点位于两个独立的基因组区域（PHGDH 中的 cg14476101 和 cg16246545 以及 SLC1A5 中的 cg02711608），假发现率低于 0.05。进一步分析揭示了血浆甘氨酸/丝氨酸水平与 DNA 甲基化之间复杂的双向关系。此外，我们观察到 DNA 甲基化在甘氨酸/丝氨酸对其代谢/转运基因表达的影响中起着很强的中介作用，中介效应的比例从 11.8%到 54.3%不等。这一结果在另一个基于人群的独立队列 Rotterdam Study 中也得到了复制。为了验证我们的发现，我们进行了体外细胞研究，证实了 DNA 甲基化在调节 PHGDH 基因表达中的中介作用。
我们的研究结果揭示了一种潜在的反馈机制，即甘氨酸和丝氨酸通过 DNA 甲基化调节基因表达。
