INO80-Dependent Remodeling of Transcriptional Regulatory Network Underlies the Progression of Heart Failure

• DOI: 10.1161/circulationaha.123.065440
• Publication Date: 2023-12-28T10:01:02Z
• Authors: Zongna Ren; Wanqing Zhao; Dandan Li; Peng Yu; Lin Mao; Quanyi Zhao; Luyan Yao; Xuelin Zhang; Yandan Liu; Bingying Zhou; Li Wang
• Keywords: Heart Failure; 0301 basic medicine; Transposases; Chromatin Assembly and Disassembly; Chromatin; DNA-Binding Proteins; Mice; 03 medical and health sciences; Humans; Animals; RNA; ATPases Associated with Diverse Cellular Activities; Gene Regulatory Networks; Myocytes, Cardiac

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.