Abstract
Myocardial infarction (MI) is a fatal heart disease with high morbidity and mortality. Various studies have demonstrated that a series of relatively specific biological events occur within 24 h of MI. However, the roles of histone modifications in this pathological process are still poorly understood. To investigate the regulation of histone modifications on gene expression in early MI, we performed RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) on myocardial tissues 24 h after the onset of MI. The genome-wide profiles of five histone marks (H3K27ac, H3K9ac, H3K4me3, H3K9me3, and H3K27me3) were explored through ChIP-seq. RNA-seq identified 1,032 differentially expressed genes (DEGs) between the MI and sham groups. ChIP-seq analysis found that 195 upregulated DEGs were modified by change of at least one of the three active histone marks (H3K27ac, H3K9ac, and H3K4me3), and the biological processes and pathways analysis showed that these DEGs were significantly enriched in cardiomyocyte differentiation and development, inflammation, angiogenesis, and metabolism. In the transcriptional regulatory network, Ets1, Etv1, and Etv2 were predicted to be involved in gene expression regulation. In addition, by integrating super-enhancers (SEs) with RNA-seq data, 76 DEGs were associated with H3K27ac-enriched SEs in the MI group, and the functions of these SE-associated DEGs were mainly related to angiogenesis. Our results suggest that histone modifications may play important roles in the regulation of gene expression in the early stage of MI, and the early angiogenesis response may be initiated by SEs.
Highlights
Myocardial infarction (MI) is a leading cause of death all over the world, mainly caused by acute coronary artery occlusion, which leads to severe myocardial ischemia, and subsequent myocardium necrosis [1]
The biological processes of the upregulated differentially expressed genes (DEGs) modified by active marks (H3K9ac, H3K27ac, and H3K4me3) were enriched in cardiomyocyte differentiation and development, inflammation, and angiogenesis
It is worth noting that inflammatory response was enriched in both function (GO) and pathway (KEGG) analysis, and H3K9ac, H3K27ac, and H3K4me3 regulated the expression of critical chemokines in the early stage of MI
Summary
Myocardial infarction (MI) is a leading cause of death all over the world, mainly caused by acute coronary artery occlusion, which leads to severe myocardial ischemia, and subsequent myocardium necrosis [1]. A considerable number of biological events occur in the early stage of MI, such as inflammation, apoptosis, autophagy, and angiogenesis, leading. Histone Modification in Myocardial Infarction to ventricular remodeling [2,3,4]. It is of great significance to explore the key molecular events and regulatory mechanisms in the early stage of MI. Histone modification is a post-translational modification including methylation, acetylation, phosphorylation, ubiquitylation, and SUMOylation, etc. [7], among which the methylation and acetylation of H3K4, H3K9, and H3K27 were common histone marks. Acetylation correlates with transcriptional activation, such as acetylation of histone H3 on lys and lys (H3K9ac and H3K27ac) [8]. The transcriptional activity of methylation modifications on lysine residues varies according to the degree and site of methylation. Tri-methylation of histone H3 on lys and lys (H3K9me and H3K27me3) represents transcriptional suppression, whereas tri-methylation on lys (H3K4me3) is associated with transcriptional activation [9, 10]
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