Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells

Luciano Pirola, Aneta Balcerczyk, Richard W. Tothill, Izhak Haviv, Antony Kaspi, Sebastian Lunke, Mark Ziemann, Tom Karagiannis, Stephen Tonna, Adam Kowalczyk, Bryan Beresford-Smith, Geoff Macintyre, Ma Kelong, Zhang Hongyu, Jingde Zhu, Assam El-Osta

Research output: Contribution to journalArticlepeer-review

185 Scopus citations

Abstract

Emerging evidence suggests that poor glycemic control mediates post-translational modifications to the H3 histone tail. We are only beginning to understand the dynamic role of some of the diverse epigenetic changes mediated by hyperglycemia at single loci, yet elevated glucose levels are thought to regulate genome-wide changes, and this still remains poorly understood. In this article we describe genome-wide histone H3K9/K14 hyperacetylation and DNA methylation maps conferred by hyperglycemia in primary human vascular cells. Chromatin immunoprecipitation (ChIP) as well as CpG methylation (CpG) assays, followed by massive parallel sequencing (ChIP-seq and CpG-seq) identified unique hyperacetylation and CpG methylation signatures with proximal and distal patterns of regionalization associative with gene expression. Ingenuity knowledge-based pathway and gene ontology analyses indicate that hyperglycemia significantly affects human vascular chromatin with the transcriptional up-regulation of genes involved in metabolic and cardiovascular disease. We have generated the first installment of a reference collection of hyperglycemia-induced chromatin modifications using robust and reproducible platforms that allow parallel sequencing-by-synthesis of immunopurified content. We uncover that hyperglycemia-mediated induction of genes and pathways associated with endothelial dysfunction occur through modulation of acetylated H3K9/K14 inversely correlated with methyl-CpG content.

Original languageEnglish
Pages (from-to)1601-1615
Number of pages15
JournalGenome Research
Volume21
Issue number10
DOIs
StatePublished - Oct 2011
Externally publishedYes

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