Dataset Information

DNA methylation status of CpG islands in normal and atherosclerotic human arteries

ABSTRACT: Abnormal epigenetic gene regulation may play a pivotal role in atherogenesis. In particular, global DNA hypomethylation potentially leading to proatherogenic gene expression, occurs in atherosclerotic lesions in humans and animal models. In order to identify genomic sequences targeted for DNA hypomethylation in atherosclerosis, we analysed the methylation status of CpG islands (CGIs) in 45 human arteries with advanced atherosclerotic lesions and 16 normal counterparts by a microarray approach. Methylation data for 10,367 CGIs revealed that a subset (1.5%) of such sequences was hypermethylated in normal arteries, in accordance with data previously obtained in peripheral blood cells. Ninety-four per cent of this CGI subset was demethylated in atherosclerotic tissue, while only 17 of normally hypomethylated CGIs was hypermethylated in diseased tissue. A functional classification of genes physically associated with differentially methylated CGIs revealed a bias towards transcription factors (42%). The latter include HOX members, NOTCH1 and FOXP1, which are known to regulate angiogenesis, dedifferentiation, cell migration and macrophage function. The methylation status of selected CGIs was validated in further 10 subjects for either group. Expression patterns of these factors were compatible with the observed differential methylation. Our data suggest that one of the molecular changes associated with aberrant DNA methylation in advanced atherosclerosis is the regulation of critical transcription factor genes for the induction of a proatherogenic cellular phenotype.

ORGANISM(S): Homo sapiens

PROVIDER: GSE15552 | GEO | 2009/04/04

SECONDARY ACCESSION(S): PRJNA115995

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Background Rupture or erosion of advanced atherosclerotic lesions with a resultant myocardial infarction or stroke are the leading worldwide cause of death. However, we have a very limited understanding of the identity, origin, and function of many cells that make up late stage atherosclerotic lesions, as well as the mechanisms by which they control plaque stability. Methods and Results Using RNAseq and ChIPseq of advanced atherosclerotic lesions from mice, we provide evidence SMC-specific Klf4- versus Oct4-knockout ApoE-/- mice showed virtually opposite genomic signatures and putative SMC Klf4 or Oct4 target genes play an important role regulating SMC phenotypic changes. Further, we conducted a comprehensive single-cell RNA-seq of advanced human carotid endarterectomy samples and compared these with scRNAseq from murine micro-dissected advanced atherosclerotic lesions with SMC and endothelial lineage tracing to survey all plaque cell types and rigorously determine their origin. This analysis revealed remarkable similarity of transcriptomic clusters between mouse and human lesions and extensive plasticity of SMC- and EC-derived lesion cells. The latter included 7 distinct clusters of SMC- and EC-derived cells, most negative for traditional markers. In particular, SMC contributed to a Myh11-, Lgals3+ population with a chondrocyte-like gene signature that was markedly reduced with SMC-specific conditional knockout of Klf4. To study these cells and the mechanisms of their transition, we developed an innovative dual lineage tracing mouse that can uniquely label and genetically target Myh11+ SMC that subsequently activate Lgals3. We observed that SMC that activate Lgals3 comprise up to 2/3 of all SMC in advanced plaques. However, initial activation of Lgals3 in these cells does not represent conversion to a terminally differentiated state, but rather represents transition of these cells to a unique stem cell marker gene+, ECM-remodeling, “pioneer” cell phenotype that are the first to invest within lesions and subsequently give rise to at least 3 other SMC phenotypes within advanced lesions including Klf4-dependent osteogenic phenotypes likely to contribute to plaque calcification and plaque destabilization. Conclusions Taken together, these results provide evidence that SMC-derived cells within advanced mouse and human atherosclerotic lesions exhibit far greater phenotypic plasticity than generally believed, with Klf4 regulating transition to multiple phenotypes including Lgals3+ osteogenic cells likely to be detrimental for late stage atherosclerosis plaque pathogenesis.

Dataset Information

DNA methylation status of CpG islands in normal and atherosclerotic human arteries

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure