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- Davegårdh, Cajsa, et al.
(författare)
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Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects
- 2017
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Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 15:1, s. 1-27
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Tidskriftsartikel (refereegranskat)abstract
- Background: Human skeletal muscle stem cells are important for muscle regeneration. However, the combined genome-wide DNA methylation and expression changes taking place during adult myogenesis have not been described in detail and novel myogenic factors may be discovered. Additionally, obesity is associated with low relative muscle mass and diminished metabolism. Epigenetic alterations taking place during myogenesis might contribute to these defects. Methods: We used Infinium HumanMethylation450 BeadChip Kit (Illumina) and HumanHT-12 Expression BeadChip (Illumina) to analyze genome-wide DNA methylation and transcription before versus after differentiation of primary human myoblasts from 14 non-obese and 14 obese individuals. Functional follow-up experiments were performed using siRNA mediated gene silencing in primary human myoblasts and a transgenic mouse model. Results: We observed genome-wide changes in DNA methylation and expression patterns during differentiation of primary human muscle stem cells (myoblasts). We identified epigenetic and transcriptional changes of myogenic transcription factors (MYOD1, MYOG, MYF5, MYF6, PAX7, MEF2A, MEF2C, and MEF2D), cell cycle regulators, metabolic enzymes and genes previously not linked to myogenesis, including IL32, metallothioneins, and pregnancy-specific beta-1-glycoproteins. Functional studies demonstrated IL-32 as a novel target that regulates human myogenesis, insulin sensitivity and ATP levels in muscle cells. Furthermore, IL32 transgenic mice had reduced insulin response and muscle weight. Remarkably, approximately 3.7 times more methylation changes (147,161 versus 39,572) were observed during differentiation of myoblasts from obese versus non-obese subjects. In accordance, DNMT1 expression increased during myogenesis only in obese subjects. Interestingly, numerous genes implicated in metabolic diseases and epigenetic regulation showed differential methylation and expression during differentiation only in obese subjects. Conclusions: Our study identifies IL-32 as a novel myogenic regulator, provides a comprehensive map of the dynamic epigenome during differentiation of human muscle stem cells and reveals abnormal epigenetic changes in obesity.
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| 3. |
- Zetterström, Maria, 1970-
(författare)
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Role of interleukin-1 in fever and inflammation
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The proinflammatory cytokines interleukin (IL) -1α, IL-1β and IL-6 are key mediators in the host's response to injury and infection. One of the systemic responses elicited by these proinflammatory cytokines, when injected peripherally or centrally, is fever. Thus, these proteins may act as endogenous pyrogens.We have shown that for a functional IL-1 mediated febrile response in vivo, both IL-1 receptor type I (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) are necessary components, as knockout (KO) mice, lacking either IL-1RI or IL-1RAcP proteins, do not mount febrile responses to rrIL-1 (25-50 μg/kg, i.p.) injections, whereas they responded with fever when challenged by LPS (50 μg/kg, i.p.). These results suggest that IL-1 induces fever via signalling through a receptor complex, consisting of both IL-1RI and IL-1RAcP. We have also shown that IL-1β cannot induce NFκB translocation to the nucleus in primary astrocyte cultures derived from IL-1RAcP KO mice, suggesting a signalling role for this protein in mouse astrocytes.When the regulation of interleukin-1β converting enzyme (ICE, caspase-1) was studied in rat after peripheral LPS treatment (2 mg/kg, i.p.), elevations were seen, on both mRNA levels and enzyme activity in the pituitary, whereas in adrenal glands, an increase of mRNA levels did not coincide with upregulated enzyme activity. However, LPS was further shown to differentially regulate ICE isoforms, some of which are supposed to act as endogenous inhibitors of ICE activity. Thus, ICE activity seems to be tightly controlled on a transcriptional level, where regulation of ICE isoforms play an important role, as well as at the post transcriptional level.We have also shown that treatment with a neurotoxic fragment of β-amyloid, βA(25-35), induces a reactive phenotype of rat primary astrocyte cultures. The progression of this reactive phenotype was shown to coincide with elevated mRNA levels of IL-1α and IL-6. In addition, βA(25-35) treatment of primary astrocyte cultures derived from IL-1RI KO mice, induced a hypersensitive IL-1α response and a decreased IL-6 response. IL-1a and IL-6 are therefore proposed to be important molecules for development of reactive gliosis, and we also propose that signalling via IL-1RI is necessary for a full-scale induction of IL-6 mRNA.
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