Conserved NPPB + Border Zone Switches From MEF2- to AP-1–Driven Gene Program

作者：Karel van Duijvenboden, Dennis E. M. de Bakker, Joyce C.K. Man, Rob Janssen, Marie Günthel, Matthew C. Hill, Ingeborg B. Hooijkaas, Ingeborg van der Made, Petra H. van der Kraak, Aryan Vink, Esther E. Creemers, James F. Martin, Phil Barnett, Jeroen Bakkers, Vincent M. Christoffels · 发表于：Circulation · 年份：2019 · DOI：10.1161/circulationaha.118.038944 · 被引用次数：107 · 研究领域：Congenital heart defects research、Cardiac Fibrosis and Remodeling、Pluripotent Stem Cells Research

BACKGROUND: Surviving cells in the postinfarction border zone are subjected to intense fluctuations of their microenvironment. Recently, border zone cardiomyocytes have been specifically implicated in cardiac regeneration. Here, we defined their unique transcriptional and regulatory properties, and comprehensively validated new molecular markers, including Nppb, encoding B-type natriuretic peptide, after infarction. METHODS: Transgenic reporter mice were used to identify the Nppb-positive border zone after myocardial infarction. Transcriptome analysis of remote, border, and infarct zones and of purified cardiomyocyte nuclei was performed using RNA-sequencing. Top candidate genes displaying border zone spatial specificity were histologically validated in ischemic human hearts. Mice in which Nppb was deleted by genome editing were subjected to myocardial infarction. Chromatin accessibility landscapes of border zone and control cardiomyocyte nuclei were assessed by using assay for transposase-accessible chromatin using sequencing. RESULTS: We identified the border zone as a spatially confined region transcriptionally distinct from the remote myocardium. The transcriptional response of the border zone was much stronger than that of the remote ventricular wall, involving acute downregulation of mitochondrial oxidative phosphorylation, fatty acid metabolism, calcium handling, and sarcomere function, and the activation of a stress-response program. Analysis of infarcted human hearts...