The epigenetic landscape of the heart in ischemia-reperfusion injury
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Abstract
Ischemic heart diseases are the leading cause of death worldwide. Cardiomyocytes detect and adapt to hypoxic and nutritional stress through immediate transcriptional, translational and metabolic responses. The environmental effects of ischemia on chromatin nanostructure were analysed by characterising and integrating chromatin structure with differential gene expression analysis. Short-term oxygen and nutrient deprivation (OND) of the cardiomyocyte cell-line HL-1 induces a previously undescribed chromatin architecture, consisting of large, chromatin sparse voids interspersed between ring-like structures. Along with chromatin compaction, histones become deacetylated and transcription is repressed. Among the regions which are affected by altered acetylation are genes previously reported to be differentially expressed in cardiac diseases.
OND induced chromatin compaction and histone deacetylation are reversible, and upon restitution of normoxia and nutrients, chromatin adopts a more open structure than in untreated cells, with in particular the expression of histone genes becoming repressed. The compacted state of chromatin reduces transcription, while the open chromatin structure, induced upon recovery, provokes a transitory increase in transcription. Mechanistically, chromatin compaction is associated with depletion of ATP and redistribution of the polyamine pool into the nucleus by mass action. Inhibition of histone deacetylation or polyamine synthesis prior to OND promotes a more relaxed chromatin structure, implicating that HDAC inhibitors could have considerable therapeutic benefit in the treatment of ischemic heart diseases.
These studies exemplify the dynamic capacity of chromatin architecture to physically respond to environmental conditions, directly link cellular energy status to chromatin compaction and provide insight into the effect ischemia has on the nuclear architecture of cells.