Liver X Receptor-Binding DNA Motif Associated With Atherosclerosis-Specific DNA Methylation Profiles of Elements and Neighboring CpG Islands.

Background: The signals that determine atherosclerosis-specific DNA methylation profiles are only partially known. We previously identified a 29-bp DNA motif (differential methylation motif [DMM]) proximal to CpG islands (CGIs) that undergo demethylation in advanced human atheromas. Those data hinted that the DMM docks modifiers of DNA methylation and transcription.

Methods And Results: We sought to functionally characterize the DMM. We showed that the DMM overlaps with the RNA polymerase III-binding B box of short interspersed nuclear elements and contains a DR2 nuclear receptor response element. Pointing to a possible functional role for an DMM, CGIs proximal (<100 bp) to near-intact DMM-harboring are significantly less methylated relative to CGIs proximal to degenerate DMM-harboring or to DMM-devoid mammalian-wide interspersed repeat short interspersed nuclear elements in human arteries. As for DMM-binding factors, LXRB (liver X receptor β) binds the DMM in a DR2-dependent fashion, and LXR (liver X receptor) agonists induce significant hypermethylation of the bulk of in THP-1 cells. Furthermore, we describe 3 intergenic long noncoding RNAs that harbor a DMM, are under transcriptional control by LXR agonists, and are differentially expressed between normal and atherosclerotic human aortas. Notably, CGIs adjacent to those long noncoding RNAs tend to be hypomethylated in symptomatic relative to stable human atheromas.

Conclusions: Collectively, the data suggest that a DMM is associated with 2 distinct methylation states: relatively low methylation of CGIs and element hypermethylation. Based on the known atheroprotective role of LXRs, we propose that LXR agonist-induced hypermethylation, a landmark of atherosclerosis, is a compensatory rather than proatherogenic response.