<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Integrated multi-omic dynamics of human adipocyte differentiation with focus on DNA hydroxymethylation and epigenomic effects of long-term docosahexaenoic acid treatment"^^ . "Metabolic Syndrome is a multifactorial metabolic disorder characterized by obesity in association with altered lipid profiles, elevated glucose levels, and/or increased blood pressure, forming a cluster of risk factors for cardiovascular diseases and type 2 diabetes. Changes in lifestyle and diet are powerful strategies in preventing the development of the metabolic syndrome. An evolving research field linked with preventable diseases is the consumption of bioactive-enriched foods since for some bioactives the dose for healthpromoting effects can only be achieved by enrichment. Docosahexaenoic acid (DHA) is an n-3 fatty acid displaying lipid-lowering activity. In the liver, DHA inhibits lipogenesis thereby promoting an improved lipid profile in the blood. However, the impact of DHA on preadipocytes, the source for new adipocytes generated during adipogenesis for additional lipid storage, remains insufficiently characterized.\r\nCell differentiation processes are controlled by epigenetic mechanisms including DNA hydroxymethylation and are associated with cell-type specific transcriptional regulation. To profile epigenetic gene regulation of our model system, I first characterized human adipocyte differentiation of Simpson-Golabi-Behmel Syndrome (SGBS) cells at the level of DNA hydroxymethylation (5hmC) using two whole-genome sequencing techniques. I observed gain in the 5hmC mark during adipocyte differentiation, particularly enriched at enhancer regions, around adipogenic transcription factor (TF) binding sites. Based on cluster analyses, I was able to describe clusters with different dynamics of hydroxymethylation associated with the binding of specific TFs. Early hydroxymethylation clusters were enriched with TF binding motifs involved, e.g., in clonal expansion at an early stage of adipogenesis. On the other hand, hydroxymethylation emerging during late adipogenesis was associated with TF binding in the second phase of chromatin remodeling, such as of the peroxisome proliferator-activated receptor gamma (PPARG) and of CCAAT/enhancer binding protein alpha (CEBPA). Integrated analysis of hydroxymethylation and gene expression recapitulated the involvement of hydroxymethylated enhancer regions in the regulation of gene expression programs characteristic of mature adipocytes. By maintaining mature adipocytes in culture for 14 days after completion of adipocyte differentiation, I could provide evidence for 5hmC as a stable epigenetic mark. In vivo relevance of these findings was confirmed by a high degree of overlap with hydroxymethylation in white adipose tissue (WAT). As 5hmC is often considered as an intermediated mark generated during DNA demethylation, I investigated potential mechanisms involved in 5hmC stabilization. I detected that acetylated nei like DNA glycosylase 1 (acNEIL1), reported previously as a hydroxymethylation binding protein, was enriched in WAT promoter and enhancer regions, but its binding was independent of the hydroxymethylation mark, especially in promoter regions. Based on metabolome data, I rather hypothesize that declining α-ketoglutarate (αKG) levels during adipogenesis could compromise ten-eleven translocation (TET)-mediated demethylation and thereby contribute to stabilization of the 5hmC mark in nonproliferating mature adipocytes.\r\nIn the second part of my thesis, I investigated the effect of long-term cultivation (3 - 4 weeks) of SGBS in the presence of low-dose DHA on genome-wide DNA methylation (EPIC array) and gene expression levels (RNA-seq). DHA-treatment\r\nresulted in massive methylation\r\ndifferences. However, these methylation differences mainly overlapped with gradual cultureassociated methylation changes. A subset of the differentially methylated CpGs was located in partially methylated domains (PMDs) associated with the nuclear lamina and characterized by late replication timing. These sites displayed gradual loss in methylation, correlating with a methylation-based mitotic score (EpiCMIT.hypo) and attributed to an impairment of DNA methylation maintenance during replication. At the gene expression level, I could separate effects directly attributable to DHA from culture-associated gene expression changes. Notably, I detected anti-inflammatory activity by reduction of tumor necrosis factor alpha (TNFα) signaling and repression of sterol regulatory element-binding protein 1/2 (SREBP1/2) signaling, possibly contributing to reduced lipogenesis and increased insulin sensitivity – two crucial mechanisms in the prevention of the metabolic syndrome.\r\nTo sum up, molecular understanding of the interplay of cellular metabolism and epigenetics in gene regulation of human adipocyte differentiation might be crucial for the deeper understanding of the development of metabolic syndrome – a disease with altered energy metabolism. Furthermore, deciphering the molecular mechanisms of DHA in human preadipocytes might help to understand how to reverse some of the adverse effects of obesity and its associated metabolic complications, showing us a path towards improved public health."^^ . "2023" . . . . . . . "Clarissa"^^ . "Feuerstein-Akgöz"^^ . "Clarissa Feuerstein-Akgöz"^^ . . . . . . "Integrated multi-omic dynamics of human adipocyte differentiation with focus on DNA hydroxymethylation and epigenomic effects of long-term docosahexaenoic acid treatment (PDF)"^^ . . . "Thesis_Clarissa_Feuerstein_Akgöz_A.pdf"^^ . . . "Integrated multi-omic dynamics of human adipocyte differentiation with focus on DNA hydroxymethylation and epigenomic effects of long-term docosahexaenoic acid treatment (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Integrated multi-omic dynamics of human adipocyte differentiation with focus on DNA hydroxymethylation and epigenomic effects of long-term docosahexaenoic acid treatment (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Integrated multi-omic dynamics of human adipocyte differentiation with focus on DNA hydroxymethylation and epigenomic effects of long-term docosahexaenoic acid treatment (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Integrated multi-omic dynamics of human adipocyte differentiation with focus on DNA hydroxymethylation and epigenomic effects of long-term docosahexaenoic acid treatment (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Integrated multi-omic dynamics of human adipocyte differentiation with focus on DNA hydroxymethylation and epigenomic effects of long-term docosahexaenoic acid treatment (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #31571 \n\nIntegrated multi-omic dynamics of human adipocyte differentiation with focus on DNA hydroxymethylation and epigenomic effects of long-term docosahexaenoic acid treatment\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . .