Rangel Salazar, RubénWickström-Lindholm, MarieAguilar Salinas, Carlos A.Alvarado-Caudillo, YolandaDøssing, Kristina B. V.Esteller, ManelLabourier, EmmanuelLund, GertrudNielsen, Finn C.Rodríguez-Ríos, DaliaSolís Martínez, Martha O.Wrobel, KatarzynaWrobel, KazimierzZaina, Silvio2018-11-302018-11-302011-11-25https://hdl.handle.net/2445/126608Background: 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.12 p.application/pdfengcc by (c) Rangel Salazar et al., 2011http://creativecommons.org/licenses/by/3.0/es/Regulació genèticaLipoproteïnesGenetic regulationLipoproteinsinfo:eu-repo/semantics/article7002592018-07-24info:eu-repo/semantics/openAccess22118513