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Human native lipoprotein-induced de novo DNA methylation is associated with repression of inflammatory genes in THP-1 macrophages

Rangel-Salazar, Ruben; Lindholm, Marie LU ; Aguilar-Salinas, Carlos A.; Alvarado-Caudillo, Yolanda; Dossing, Kristina Bv; Esteller, Manel; Labourier, Emmanuel; Lund, Gertrud; Nielsen, Finn C. and Rodriguez-Rios, Dalia, et al. (2011) In BMC Genomics 12.
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... (More)
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. (Less)
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BMC Genomics
volume
12
publisher
BioMed Central
external identifiers
  • wos:000298590300001
  • scopus:82055171836
ISSN
1471-2164
DOI
10.1186/1471-2164-12-582
language
English
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yes
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fc81de0c-6ec3-4290-9a73-34f436957f7e (old id 2348592)
date added to LUP
2012-03-01 11:22:02
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2017-08-06 04:00:10
@article{fc81de0c-6ec3-4290-9a73-34f436957f7e,
  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/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.},
  author       = {Rangel-Salazar, Ruben and Lindholm, Marie and Aguilar-Salinas, Carlos A. and Alvarado-Caudillo, Yolanda and Dossing, Kristina Bv and Esteller, Manel and Labourier, Emmanuel and Lund, Gertrud and Nielsen, Finn C. and Rodriguez-Rios, Dalia and Solis-Martinez, Martha O. and Wrobel, Katarzyna and Wrobel, Kazimierz and Zaina, Silvio},
  issn         = {1471-2164},
  language     = {eng},
  publisher    = {BioMed Central},
  series       = {BMC Genomics},
  title        = {Human native lipoprotein-induced de novo DNA methylation is associated with repression of inflammatory genes in THP-1 macrophages},
  url          = {http://dx.doi.org/10.1186/1471-2164-12-582},
  volume       = {12},
  year         = {2011},
}