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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/126608
Human native lipoprotein-induced de novo DNA methylation is associated with repression of inflammatory genes in THP-1 macrophages
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Background: We previously showed that a VLDL-and LDL-rich mix of human native lipoproteins induces a set of repressive epigenetic marks, i. e. de novo DNA methylation, histone 4 hypoacetylation and histone 4 lysine 20 (H4K20) hypermethylation in THP-1 macrophages. Here, we: 1) ask what gene expression changes accompany these epigenetic responses; 2) test the involvement of candidate factors mediating the latter. We exploited genome expression arrays to identify target genes for lipoprotein-induced silencing, in addition to RNAi and expression studies to test the involvement of candidate mediating factors. The study was conducted in human THP-1 macrophages. Results: Native lipoprotein-induced de novo DNA methylation was associated with a general repression of various critical genes for macrophage function, including pro-inflammatory genes. Lipoproteins showed differential effects on epigenetic marks, as de novo DNA methylation was induced by VLDL and to a lesser extent by LDL, but not by HDL, and VLDL induced H4K20 hypermethylation, while HDL caused H4 deacetylation. The analysis of candidate factors mediating VLDL-induced DNA hypermethylation revealed that this response was: 1) surprisingly, mediated exclusively by the canonical maintenance DNA methyltransferase DNMT1, and 2) independent of the Dicer/microRNA pathway. Conclusions: Our work provides novel insights into epigenetic gene regulation by native lipoproteins. Furthermore, we provide an example of DNMT1 acting as a de novo DNA methyltransferase independently of canonical de novo enzymes, and show proof of principle that de novo DNA methylation can occur independently of a functional Dicer/micro-RNA pathway in mammals.
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RANGEL SALAZAR, Rubén, WICKSTRÖM-LINDHOLM, Marie, AGUILAR SALINAS, Carlos a., ALVARADO-CAUDILLO, Yolanda, DØSSING, Kristina b. v., ESTELLER, Manel, LABOURIER, Emmanuel, LUND, Gertrud, NIELSEN, Finn c., RODRÍGUEZ-RÍOS, Dalia, SOLÍS MARTÍNEZ, Martha o., WROBEL, Katarzyna, WROBEL, Kazimierz, ZAINA, Silvio. Human native lipoprotein-induced de novo DNA methylation is associated with repression of inflammatory genes in THP-1 macrophages. _BMC Genomics_. 2011. Vol. 12, núm. 582. [consulta: 20 de gener de 2026]. [Disponible a: https://hdl.handle.net/2445/126608]