Biology subjects

Sinke, L.

Publications and source records attributed to Sinke, L..

3 recordsLinked to original sources

bioRxiv2024

DNA methylation and gene expression trajectories of human postprandial metabolism

Human postprandial metabolism is characterised by a highly individualised response to food that is predictive of cardiometabolic health and underexplored at the molecular level. We profiled blood DNA methylation (DNAm) and gene expression trajectories before and after a test meal in 225 European participants. We identify DNAm changes at fasting, 30 minutes and 4 hours after meal challenge, including in metabolically relevant genes INPP4A, GHRL, ASIP and ABCG1, with changes observed as early as 30mins postprandially. Gene expression trajectories also changed postprandially predominantly at 4 hours, with replication of lipid metabolism (CPT1A) and circadian rhythm (PER1) genes. Genetic variants affect postprandial molecular trajectories at genes linked to obesity (PDE9A) and glucose response (GPT2). Multiple signals associated with postprandial glucose and triglyceride levels, with replication of CPT1A methylation. The postprandial DNAm and expression trajectories target metabolically relevant genes, giving insights towards mechanisms underlying inter-individual response to food and cardiometabolic disease risk.

genomics↗

bioRxiv2024

Oleic acid triggers CD4+ T cells to be metabolically rewired and poised to differentiate into proinflammatory T cell subsets upon activation

T cells are the most common immune cells in atherosclerotic plaques and the function of T cells can be altered by fatty acids. Here, we show that pre-exposure of CD4+ T cells to oleic acid, an abundant fatty acid linked to cardiovascular events, results in a preferential differentiation into pro-inflammatory subsets upon activation by upregulating core metabolic pathways. RNA-sequencing of non-activated CD4+ T cells revealed that oleic acid upregulates genes encoding enzymes responsible for cholesterol and fatty acid biosynthesis. Transcription footprint analysis linked this rewiring to the differentiation of pro-inflammatory subsets. Indeed, spectral flow cytometry showed that pre-exposure to oleic acid results in a skew toward IL-9, IL-17A, IL-5 and IL-13 producing T cells upon activation. Importantly, inhibition of either cholesterol or fatty acid biosynthesis abolishes this effect, suggesting a beneficial role for statins beyond cholesterol lowering. Taken together, fatty acids may affect inflammatory diseases by influencing T cell metabolism.

genomics↗

bioRxiv2023

The inactive X chromosome accumulates widespread epigenetic variability with age

BackgroundLoss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome in females through DNA methylation. Hence, age-related disruption of X-chromosome inactivation (XCI) may contribute to the ageing process in women. MethodsWe analyzed 9,777 CpGs on the X chromosome in whole blood samples from 2343 females and 1688 males. We replicated findings in duplicate using one whole blood and one purified monocyte data set (in total, 991/924 females/males). We used double generalized linear models (DGLM) to detect age-related differentially methylated CpGs (aDMCs), whose mean methylation level differs with age, and age-related variable methylated CpGs (aVMCs), whose methylation level becomes more variable with age. ResultsIn females, aDMCs were relatively uncommon (n=33) and preferentially occurred in regions known to escape XCI. In contrast, many CpGs (n=987) were found to display an increased variance with age (aVMCs). Of note, the replication rate of aVMCs was also high in purified monocytes (95%), indicating that their occurrence may be independent of cell composition. aVMCs accumulated in CpG islands and regions subject to XCI. Although few aVMCs were associated with X-linked genes in all females studied, an exploratory analysis suggested that such associations may be more common in old females. In males, aDMCs (n=316) were primarily driven by cell composition, while aVMCs replicated well (94%) but were infrequent (n=37). ConclusionsAge-related DNA methylation differences at the inactive X chromosome are dominated by the accumulation of variability.

genetics↗