Abstract P2072: Complex Remodeling Of Transcriptomes And Chromatin Accessibility Epigenomes In Acute Post-infarct Myocardium Revealed By Massive Parallel Single-nucleus Sequencing Analyses

Abstract

Background: Adverse remodeling in post-infarct myocardium includes weakened contractility due to substantial cardiomyocyte (CM) loss, augmented inflammatory and fibrotic responses, and re-organization of vasculatures. Current mechanistic understanding of cellular interaction within and between cardiac cell populations in post-injured myocardium remained limited. Aims: To identify molecular regulations converged in post-infarct heart cells. Methods and Results: We simultaneously analyzed total heart cells in post-infarct myocardium by using the latest single-nucleus (sn) dual transcriptomics-epigenomics approaches (snRNA-seq and snATAC-seq) in our new triple-transgenic multi-reporter mouse model featuring CM lineage tracking and maturity visualization. The compositions of cell types clustered based on transcriptomic profiles are highly comparable to those identified by open chromatin accessibility. There were significant reductions of CMs and endothelial cells, along with remarkable increases of immuno/inflammatory cells and cardiac fibroblasts in post-infarct hearts compared to controls, as revealed by comparable cell populations clustered based on transcriptomic profiles versus epigenomics chromatin accessibility profiles. We characterized the dual-omic molecular signatures of all heart cell populations from acute post-infarct murine hearts in contrast to controls. We identified the features as various molecular states in pseudotime trajectory, distinguishing each cell population and sub-cluster presented in diseased and normal hearts. Heart cells in post-infarct myocardium were clustered along the newer pseudotime series while those in control hearts were mostly located in earlier phases of the pseudotime trajectory. Lastly, we identified the signaling pathways and TFs enriched by differentially-expressed genes (DEGs) and the differentially active regions (DARs) of the chromatin in dedifferentiated CMs as well as other heart cell types and their relationships in post-MI and normal hearts. Conclusions: The results demonstrated the complex cellular and molecular remodeling at single-cell (nucleus) level in acute post-infarct hearts in which diverse and converging signaling networks may be targeted for heart failure therapeutics.