title: Human native lipoprotein-induced de novo DNA methylation is associated with repression of inflammatory genes in THP-1 macrophages.
abstract: 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/micro-RNA 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.
authors: Department of Medical Sciences, University of Guanajuato, León, Mexico.
authors: Rubén
authors: R
authors: Rangel-Salazar
authors: Marie
authors: M
authors: Wickström-Lindholm
authors: Carlos A
authors: CA
authors: Aguilar-Salinas
authors: Yolanda
authors: Y
authors: Alvarado-Caudillo
authors: Kristina B V
authors: KB
authors: Døssing
authors: Manel
authors: M
authors: Esteller
authors: Emmanuel
authors: E
authors: Labourier
authors: Gertrud
authors: G
authors: Lund
authors: Finn C
authors: FC
authors: Nielsen
authors: Dalia
authors: D
authors: Rodríguez-Ríos
authors: Martha O
authors: MO
authors: Solís-Martínez
authors: Katarzyna
authors: K
authors: Wrobel
authors: Kazimierz
authors: K
authors: Wrobel
authors: Silvio
authors: S
authors: Zaina
mesh_terms: D002460:Cell Line; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008074:Lipoproteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D040901:Proteomics
chemical_list: D006657:Histones; D008074:Lipoproteins; D035683:MicroRNAs