Blood triglyceride levels are associated with DNA methylation at the serine metabolism gene PHGDH

Truong, Vinh; Huang, Siying; Dennis, Jessica; Lemire, Mathieu; Zwingerman, Nora; Aïssi, Dylan; Kassam, Irfahan; Perret, Claire; Wells, Philip S.; Morange, Pierre‐Emmanuel; Wilson, Michael D.; Trégouët, David‐Alexandre; Gagnon, France

doi:10.1038/s41598-017-09552-z

Cited by 35 publications

(27 citation statements)

References 73 publications

(93 reference statements)

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“…Methylation levels at ABCG1 (cg27243685) were additionally reported in relation to occurrence of CVD events [ 24 ▪ ]. The authors further showed that triglyceride levels were associated with DNA methylation in the serine metabolism gene PHGDH encoding D-3-phosphoglycerate dehydrogenase (cg14476101), a result confirmed by Truong et al [ 30 ]. Public database findings support a functional role of cg1476101 in PHGDH expression [ 30 ].…”

Section: Newly Discovered Cpg Sites and Their Level Of Evidencementioning

confidence: 62%

DNA methylation in human lipid metabolism and related diseases

Mittelstraß

Waldenberger

2018

Current Opinion in Lipidology

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Purpose of reviewIt is becoming increasingly evident that epigenetic mechanisms, particularly DNA methylation, play a role in the regulation of blood lipid levels and lipid metabolism-linked phenotypes and diseases.Recent findingsRecent genome-wide methylation and candidate gene studies of blood lipids have highlighted several robustly replicated methylation markers across different ethnicities. Furthermore, many of these lipid-related CpG sites associated with blood lipids are also linked to lipid-related phenotypes and diseases. Integrating epigenome-wide association studies (EWAS) data with other layers of molecular data such as genetics or the transcriptome, accompanied by relevant statistical methods (e.g. Mendelian randomization), provides evidence for causal relationships. Recent data suggest that epigenetic changes can be consequences rather than causes of dyslipidemia. There is sparse information on many lipid classes and disorders of lipid metabolism, and also on the interplay of DNA methylation with other epigenetic layers such as histone modifications and regulatory RNAs.SummaryThe current review provides a literature overview of epigenetic modifications in lipid metabolism and other lipid-related phenotypes and diseases focusing on EWAS of DNA methylation from January 2016 to September 2017. Recent studies strongly support the importance of epigenetic modifications, such as DNA methylation, in lipid metabolism and related diseases for relevant biological insights, reliable biomarkers, and even future therapeutics.

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Section: Newly Discovered Cpg Sites and Their Level Of Evidencementioning

confidence: 62%

DNA methylation in human lipid metabolism and related diseases

Mittelstraß

Waldenberger

2018

Current Opinion in Lipidology

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“…Thus, we performed H3K4me3 ChIP on Ewing sarcoma cells before and after exposure to MI‐503 and assessed the levels of enrichment in intron 1 of the PHGDH gene. This epigenetic regulatory region was defined based on previously demonstrated enrichment of H3K4me3 in Ewing sarcoma, and the presence of a PHGDH promoter‐associated CpG island . H3K4me3 enrichment at this PHGDH regulatory region was confirmed to be high at baseline and was reproducibly diminished after MI‐503 treatment (Figure D).…”

Section: Resultsmentioning

confidence: 91%

Menin regulates the serine biosynthetic pathway in Ewing sarcoma

Svoboda

Teh

Sud

et al. 2018

The Journal of Pathology

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Developmental transcription programs are epigenetically regulated by multi-protein complexes, including the menin- and MLL-containing trithorax (TrxG) complexes, which promote gene transcription by depositing the H3K4me3 activating mark at target gene promoters. We recently reported that in Ewing sarcoma, MLL1 (lysine methyltransferase 2A, KMT2A) and menin are overexpressed and function as oncogenes. Small molecule inhibition of the menin-MLL interaction leads to loss of menin and MLL1 protein expression, and to inhibition of growth and tumorigenicity. Here, we have investigated the mechanistic basis of menin-MLL-mediated oncogenic activity in Ewing sarcoma. Bromouridine sequencing (Bru-seq) was performed to identify changes in nascent gene transcription in Ewing sarcoma cells, following exposure to the menin-MLL interaction inhibitor MI-503. Menin-MLL inhibition resulted in early and widespread reprogramming of metabolic processes. In particular, the serine biosynthetic pathway (SSP) was the pathway most significantly affected by MI-503 treatment. Baseline expression of SSP genes and proteins (PHGDH, PSAT1, and PSPH), and metabolic flux through the SSP were confirmed to be high in Ewing sarcoma. In addition, inhibition of PHGDH resulted in reduced cell proliferation, viability, and tumor growth in vivo, revealing a key dependency of Ewing sarcoma on the SSP. Loss of function studies validated a mechanistic link between menin and the SSP. Specifically, inhibition of menin resulted in diminished expression of SSP genes, reduced H3K4me3 enrichment at the PHGDH promoter, and complete abrogation of de novo serine and glycine biosynthesis, as demonstrated by metabolic tracing studies with C-labeled glucose. These data demonstrate that the SSP is highly active in Ewing sarcoma and that its oncogenic activation is maintained, at least in part, by menin-dependent epigenetic mechanisms involving trithorax complexes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley& Sons, Ltd.

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“…It is an essential precursor of sphingolipids, which are also involved in lipid metabolism. In particular, the level of triglycerides has been associated with the serine metabolism 55 , which could establish a link between methane metabolism and lipid involvement in AD (vide infra).…”

Section: Smd-admentioning

confidence: 99%

Blood biomarkers indicate that the preclinical stages of Alzheimer's disease present overlapping molecular features

Costanzo

Paris

Melck

et al. 2020

Sci Rep

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It is still debated whether non-specific preclinical symptoms of Alzheimer’s disease (AD) can have diagnostic relevance. We followed the evolution from cognitively normal to AD by NMR-based metabolomics of blood sera. Multivariate statistical analysis of the NMR profiles yielded models that discriminated subjective memory decline (SMD), mild cognitive impairment (MCI) and AD. We validated a panel of six statistically significant metabolites that predicted SMD, MCI and AD in a blind cohort with sensitivity values ranging from 88 to 95% and receiver operating characteristic values from 0.88 to 0.99. However, lower values of specificity, accuracy and precision were observed for the models involving SMD and MCI, which is in line with the pathological heterogeneity indicated by clinical data. This excludes a “linear” molecular evolution of the pathology, pointing to the presence of overlapping “gray-zones” due to the reciprocal interference of the intermediate stages. Yet, the clear difference observed in the metabolic pathways of each model suggests that pathway dysregulations could be investigated for diagnostic purposes.

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Blood triglyceride levels are associated with DNA methylation at the serine metabolism gene PHGDH

Cited by 35 publications

References 73 publications

DNA methylation in human lipid metabolism and related diseases

DNA methylation in human lipid metabolism and related diseases

Menin regulates the serine biosynthetic pathway in Ewing sarcoma

Blood biomarkers indicate that the preclinical stages of Alzheimer's disease present overlapping molecular features

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