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Epigenome-wide association study on the plasma metabolome suggests self-regulation of the glycine and serine pathway through DNA methylation.
Wu, Jiafei; Palasantzas, Victoria; Andreu-Sánchez, Sergio; Plösch, Torsten; Leonard, Sam; Li, Shuang; Bonder, Marc Jan; Westra, Harm-Jan; van Meurs, Joyce; Ghanbari, Mohsen; Franke, Lude; Zhernakova, Alexandra; Fu, Jingyuan; Hoogerland, Joanne A; Zhernakova, Daria V.
Affiliation
  • Wu J; Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
  • Palasantzas V; Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
  • Andreu-Sánchez S; Department of Pediatrics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
  • Plösch T; Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
  • Leonard S; Department of Pediatrics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
  • Li S; Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • Bonder MJ; Perinatal Neurobiology Research Group, Department of Pediatrics, School of Medicine and Health Sciences, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany.
  • Westra HJ; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • van Meurs J; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Ghanbari M; Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
  • Franke L; Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
  • Zhernakova A; Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
  • Fu J; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Hoogerland JA; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Zhernakova DV; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Clin Epigenetics ; 16(1): 104, 2024 Aug 13.
Article in En | MEDLINE | ID: mdl-39138531
ABSTRACT

BACKGROUND:

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.

RESULTS:

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.

CONCLUSIONS:

Our findings reveal a potential feedback mechanism in which glycine and serine regulate gene expression through DNA methylation.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Serine / DNA Methylation / Epigenesis, Genetic / Genome-Wide Association Study / Metabolome / Glycine Limits: Adult / Aged / Female / Humans / Male / Middle aged Language: En Journal: Clin Epigenetics Year: 2024 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Serine / DNA Methylation / Epigenesis, Genetic / Genome-Wide Association Study / Metabolome / Glycine Limits: Adult / Aged / Female / Humans / Male / Middle aged Language: En Journal: Clin Epigenetics Year: 2024 Document type: Article Affiliation country: Country of publication: