@entity1 native lipoprotein-induced de novo DNA methylation is associated with repression of inflammatory genes in XXXX macrophages.

@entity1 @entity1357 @entity376 @entity16610
BACKGROUND: We previously showed that a VLDL- and LDL-rich mix of @entity1 native lipoproteins induces a set of repressive epigenetic marks, i.e. de novo DNA methylation, histone 4 hypoacetylation and histone 4 @entity376 20 (H4K20) hypermethylation in @entity1357 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 @entity1 @entity1357 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 @entity16610 , 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 @entity16610 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.
