H3K27ac histone acetylome changes contribute to the phenotypic response in heart diseases, particularly in end-stage heart failure. However, such epigenetic alterations have not been systematically investigated in remodeled non-failing human hearts. Therefore, valuable insight into cardiac dysfunction in early remodeling is lacking. This study aimed to reveal the acetylation changes of chromatin regions in response to myocardial remodeling and their correlations to transcriptional changes of neighboring genes. We detected chromatin regions with differential acetylation activity (DARs; Padj. < 0.05) between remodeled non-failing patient hearts and healthy donor hearts. The acetylation level of the chromatin region correlated with its RNA polymerase II occupancy level and the mRNA expression level of its adjacent gene per sample. Annotated genes from DARs were enriched in disease-related pathways, including fibrosis and cell metabolism regulation. DARs that change in the same direction have a tendency to cluster together, suggesting the well-reorganized chromatin architecture that facilitates the interactions of regulatory domains in response to myocardial remodeling. We further show the differences between the acetylation level and the mRNA expression level of cell-type-specific markers for cardiomyocytes and 11 non-myocyte cell types. Notably, we identified transcriptome factor (TF) binding motifs that were enriched in DARs and defined TFs that were predicted to bind to these motifs. We further showed 64 genes coding for these TFs that were differentially expressed in remodeled myocardium when compared with controls. Our study reveals extensive novel insight on myocardial remodeling at the DNA regulatory level. Differences between the acetylation level and the transcriptional level of cell-type-specific markers suggest additional mechanism(s) between acetylome and transcriptome. By integrating these two layers of epigenetic profiles, we further provide promising TF-encoding genes that could serve as master regulators of myocardial remodeling. Combined, our findings highlight the important role of chromatin regulatory signatures in understanding disease etiology.

中文翻译：

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H3K27ac 乙酰化组特征揭示了重塑的非衰竭人类心脏中的表观基因组重组。

H3K27ac 组蛋白乙酰组变化有助于心脏病，特别是终末期心力衰竭的表型反应。然而，这种表观遗传改变尚未在重塑的非衰竭人类心脏中进行系统研究。因此，缺乏对早期重构中心脏功能障碍的有价值的见解。本研究旨在揭示心肌重塑时染色质区域的乙酰化变化及其与邻近基因转录变化的相关性。我们检测到重构的非衰竭患者心脏和健康供体心脏之间具有差异乙酰化活性的染色质区域（DAR；Padj < 0.05）。染色质区域的乙酰化水平与其 RNA 聚合酶 II 占用水平以及每个样本的相邻基因的 mRNA 表达水平相关。DAR 的注释基因富含疾病相关途径，包括纤维化和细胞代谢调节。以相同方向变化的 DAR 倾向于聚集在一起，表明重组良好的染色质结构有助于调节域相互作用以响应心肌重塑。我们进一步显示了心肌细胞和 11 种非心肌细胞类型的细胞类型特异性标记物的乙酰化水平和 mRNA 表达水平之间的差异。值得注意的是，我们鉴定了在 DAR 中富集的转录组因子 (TF) 结合基序，并定义了预计与这些基序结合的 TF。我们进一步显示了编码这些 TF 的 64 个基因，与对照相比，这些基因在重塑的心肌中差异表达。我们的研究揭示了 DNA 调控水平上心肌重塑的广泛新颖见解。细胞类型特异性标记物的乙酰化水平和转录水平之间的差异表明乙酰化组和转录组之间存在其他机制。通过整合这两层表观遗传图谱，我们进一步提供了有前途的 TF 编码基因，可以作为心肌重塑的主要调节因子。综上所述，我们的研究结果强调了染色质调控特征在理解疾病病因学中的重要作用。