Open Access Research article

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

Rubén Rangel-Salazar1, Marie Wickström-Lindholm2, Carlos A Aguilar-Salinas3, Yolanda Alvarado-Caudillo1, Kristina BV Døssing5, Manel Esteller4, Emmanuel Labourier6, Gertrud Lund7, Finn C Nielsen5, Dalia Rodríguez-Ríos7, Martha O Solís-Martínez1, Katarzyna Wrobel8, Kazimierz Wrobel8 and Silvio Zaina125*

  • * Corresponding author: Silvio Zaina szaina@ugto.mx

  • † Equal contributors

Author Affiliations

1 Department of Medical Sciences, University of Guanajuato, León, Mexico

2 Experimental Cardiovascular Research Laboratory, Lund University, Malmö, Sweden

3 National Institute for Medical Sciences and Nutrition "S. Zubirán", Mexico City, Mexico

4 Cancer Epigenetics and Biology Program, IDIBELL, Barcelona, Spain

5 Center for Genomic Medicine, Rigshospitalet, Copenhagen, Denmark

6 Asuragen Inc., Austin, Texas

7 Department of Genetic Engineering, CINVESTAV, Irapuato, Mexico

8 Department of Chemistry, University of Guanajuato, Guanajuato, Mexico

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BMC Genomics 2011, 12:582  doi:10.1186/1471-2164-12-582

Published: 25 November 2011

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.