Browsing by Subject "WIDE DNA METHYLATION"

Sort by: Order: Results:

Now showing items 1-3 of 3
  • Clark, Christine; Palta, Priit; Joyce, Christopher J.; Scott, Carol; Grundberg, Elin; Deloukas, Panos; Palotie, Aarno; Coffey, Alison J. (2012)
  • Bacos, Karl; Gillberg, Linn; Volkov, Petr; Olsson, Anders H.; Hansen, Torben; Pedersen, Oluf; Gjesing, Anette Prior; Eiberg, Hans; Tuomi, Tiinamaija; Almgren, Peter; Groop, Leif; Eliasson, Lena; Vaag, Allan; Dayeh, Tasnim; Ling, Charlotte (2016)
    Aging associates with impaired pancreatic islet function and increased type 2 diabetes (T2D) risk. Here we examine whether age-related epigenetic changes affect human islet function and if blood-based epigenetic biomarkers reflect these changes and associate with future T2D. We analyse DNA methylation genome-wide in islets from 87 non-diabetic donors, aged 26-74 years. Aging associates with increased DNA methylation of 241 sites. These sites cover loci previously associated with T2D, for example, KLF14. Blood-based epigenetic biomarkers reflect age-related methylation changes in 83 genes identified in human islets (for example, KLF14, FHL2, ZNF518B and FAM123C) and some associate with insulin secretion and T2D. DNA methylation correlates with islet expression of multiple genes, including FHL2, ZNF518B, GNPNAT1 and HLTF. Silencing these genes in beta-cells alter insulin secretion. Together, we demonstrate that blood-based epigenetic biomarkers reflect age-related DNA methylation changes in human islets, and associate with insulin secretion in vivo and T2D.
  • Davegardh, C; Sall, J; Benrick, A; Broholm, C; Volkov, P; Perfilyev, A; Henriksen, TI; Wu, Y; Hjort, L; Brons, C; Hansson, O; Pedersen, M; Wurthner, JU; Pfeffer, K; Nilsson, E; Vaag, A; Stener-Victorin, E; Pircs, K; Scheele, C; Ling, C (2021)
    Insulin resistance and lower muscle quality (strength divided by mass) are hallmarks of type 2 diabetes (T2D). Here, we explore whether alterations in muscle stem cells (myoblasts) from individuals with T2D contribute to these phenotypes. We identify VPS39 as an important regulator of myoblast differentiation and muscle glucose uptake, and VPS39 is downregulated in myoblasts and myotubes from individuals with T2D. We discover a pathway connecting VPS39-deficiency in human myoblasts to impaired autophagy, abnormal epigenetic reprogramming, dysregulation of myogenic regulators, and perturbed differentiation. VPS39 knockdown in human myoblasts has profound effects on autophagic flux, insulin signaling, epigenetic enzymes, DNA methylation and expression of myogenic regulators, and gene sets related to the cell cycle, muscle structure and apoptosis. These data mimic what is observed in myoblasts from individuals with T2D. Furthermore, the muscle of Vps39(+/-) mice display reduced glucose uptake and altered expression of genes regulating autophagy, epigenetic programming, and myogenesis. Overall, VPS39-deficiency contributes to impaired muscle differentiation and reduced glucose uptake. VPS39 thereby offers a therapeutic target for T2D. Insulin resistance and lower muscle strength in relation to mass are hallmarks of type 2 diabetes. Here, the authors report alterations in muscle stem cells from individuals with type 2 diabetes that may contribute to these phenotypes through VPS39 mediated effects on autophagy and epigenetics.