BACKGROUND:Progressive remodeling of cardiac gene expression underlies decline in cardiac function, eventually leading to heart failure. However, the major determinants of transcriptional network switching from normal to failed hearts remain to be determined.METHODS:In this study, we integrated human samples, genetic mouse models, and genomic approaches, including bulk RNA sequencing, single-cell RNA sequencing, chromatin immunoprecipitation followed by high-throughput sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing, to identify the role of chromatin remodeling complex INO80 in heart homeostasis and dysfunction.RESULTS:The INO80 chromatin remodeling complex was abundantly expressed in mature cardiomyocytes, and its expression further increased in mouse and human heart failure. Cardiomyocyte-specific overexpression of Ino80, its core catalytic subunit, induced heart failure within 4 days. Combining RNA sequencing, chromatin immunoprecipitation followed by high-throughput sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing, we revealed INO80 overexpression-dependent reshaping of the nucleosomal landscape that remodeled a core set of transcription factors, most notably the MEF2 (Myocyte Enhancer Factor 2) family, whose target genes were closely associated with cardiac function. Conditional cardiomyocyte-specific deletion of Ino80 in an established mouse model of heart failure demonstrated remarkable preservation of cardiac function.CONCLUSIONS:In summary, our findings shed light on the INO80-dependent remodeling of the chromatin landscape and transcriptional networks as a major mechanism underlying cardiac dysfunction in heart failure, and suggest INO80 as a potential preventative or interventional target.

中文翻译：

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INO80 依赖性转录调节网络重塑是心力衰竭进展的基础

背景：心脏基因表达的渐进性重塑是心脏功能下降的基础，最终导致心力衰竭。然而，转录网络从正常心脏切换到衰竭心脏的主要决定因素仍有待确定。 方法：在这项研究中，我们整合了人类样本、遗传小鼠模型和基因组方法，包括批量 RNA 测序、单细胞 RNA 测序、染色质免疫沉淀后进行高通量测序，并通过高通量测序检测转座酶可及的染色质，以确定染色质重塑复合物 INO80 在心脏稳态和功能障碍中的作用。 结果：INO80 染色质重塑复合物在成熟心肌细胞中大量表达，其表达在小鼠和人类心力衰竭中进一步增加。心肌细胞特异性过度表达Ino80（其核心催化亚基），可在 4 天内诱导心力衰竭。将 RNA 测序、染色质免疫沉淀和高通量测序以及转座酶可及染色质分析与高通量测序相结合，我们揭示了 INO80 过度表达依赖性的核小体景观重塑，从而重塑了一组核心转录因子，尤其是 MEF2 （心肌细胞增强因子2）家族，其靶基因与心脏功能密切相关。在已建立的心力衰竭小鼠模型中，条件性心肌细胞特异性删除Ino80表现出显着的心脏功能保存。结论：总而言之，我们的研究结果揭示了染色质景观和转录网络的 INO80 依赖性重塑是心脏功能的主要机制。心力衰竭的功能障碍，并建议 INO80 作为潜在的预防或干预目标。