Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease

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  • Maja Dembic, Univ Southern Denmark, University of Southern Denmark, Dept Biochem & Mol Biol
  • ,
  • Henriette S. Andersen, Univ Southern Denmark, University of Southern Denmark, Dept Biochem & Mol Biol
  • ,
  • Jean Bastin, Univ Paris 05, DISERM UMR S 1124, UFR Biomed St Peres
  • ,
  • Thomas K. Doktor, Univ Southern Denmark, University of Southern Denmark, Dept Biochem & Mol Biol
  • ,
  • Thomas J. Corydon
  • Jorn Oliver Sass, Univ Appl Sci, IFGA
  • ,
  • Alexandra Lopes Costa, Univ Paris 05, DISERM UMR S 1124, UFR Biomed St Peres
  • ,
  • Fatima Djouadi, Univ Paris 05, DISERM UMR S 1124, UFR Biomed St Peres
  • ,
  • Brage S. Andresen, Univ Southern Denmark, University of Southern Denmark, Dept Biochem & Mol Biol

Resveratrol (RSV) is a small compound first identified as an activator of sirtuin 1 (SIRT1), a key factor in mediating the effects of caloric restriction. Since then, RSV received great attention for its widespread beneficial effects on health and in connection to many diseases. RSV improves the metabolism and the mitochondria] function, and more recently it was shown to restore fatty acid beta-oxidation (FAO) capacities in patient fibroblasts harboring mutations with residual enzyme activity. Many of RSV's beneficial effects are mediated by the transcriptional coactivator PGC-1 alpha, a direct target of SIRT1 and a master regulator of the mitochondrial fatty acid oxidation. Despite numerous studies RSV's mechanism of action is still not completely elucidated. Our aim was to investigate the effects of RSV on gene regulation on a wide scale, possibly to detect novel genes whose up regulation by RSV may be of interest with respect to disease treatment. We performed Next Generation Sequencing of RNA on normal fibroblasts treated with RSV. To investigate whether the effects of RSV are mediated through SIRT1 we expanded the analysis to include SIRT1-knockdown fibroblasts. We identified the aspartoacylase (ASPA) gene, mutated in Canavan disease, to be strongly up-regulated by RSV in several cell lines, including Canavan disease fibroblasts. We further link RSV to the up-regulation of other genes involved in myelination including the glial specific transcription factors POU3F1, POU3F2, and myelin basic protein (MBP). We also observe a strong up-regulation by RSV of the riboflavin transporter gene SLC52a1. Mutations in SLC52a1 cause transient multiple acyl-CoA dehydrogenase deficiency (MADD). Our analysis of alternative splicing identified novel metabolically important genes affected by RSV, among which is particularly interesting the alpha subunit of the stimulatory G protein (Gs alpha), which regulates the cellular levels of cAMP through adenylyl cyclase.

We conclude that in fibroblasts RSV stimulates the PGC-1 alpha and p53 pathways, and up-regulates genes affecting the glucose metabolism, mitochondrial beta-oxidation, and mitochondrial biogenesis. We further confirm that RSV might be a relevant treatment in the correction of FAO deficiencies and we suggest that treatment in other metabolic disorders including Canavan disease and MADD might be also beneficial.

OriginalsprogEngelsk
TidsskriftMolecular Genetics and Metabolism
Vol/bind126
Nummer1
Sider (fra-til)64-76
Antal sider13
ISSN1096-7192
DOI
StatusUdgivet - jan. 2019

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