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H3K27me3-mediated silencing of structural genes is required for zebrafish heart regeneration

ABSTRACT: Deciphering the genetic and epigenetic regulation of cardiomyocyte proliferation in organisms capable of robust cardiac renewal represents an attractive inroad towards regenerating the human heart. In the highly regenerative zebrafish heart, cardiomyocytes near the wound edge undergo dramatic changes in gene expression concomitant with sarcomere disassembly, loss of cell-cell adhesion, and detachment from the extracellular matrix (ECM), which leaves them poised to divide and give rise to new muscle cells that colonize the wound. Using integrated highthroughput transcriptional and chromatin analyses, we identified correlations between gene expression changes and activating H3K4me3 and/or repressive H3K27me3 dynamics8 in cardiomyocytes following injury. Within the category of downregulated genes that gain H3K27me3, transcripts encoding sarcomere and cytoskeletal components were significantly overrepresented. To investigate a functional requirement for H3K27me3-mediated gene silencing during zebrafish heart regeneration, we generated an inducible transgenic strain expressing a mutant version of histone 3, H3.3K27M, which allowed us to inhibit H3K27me3 catalysis in cardiomyocytes during the regenerative window. Hearts composed of H3.3K27M-expressing cardiomyocytes fail to regenerate with wound edge myocardium showing heightened expression of structural genes and prominent sarcomere structures. Although cell cycle re-entry was unperturbed, cytokinesis and wound invasion were significantly compromised. Collectively, our study identifies a requirement for H3K27me3-mediated silencing of structural genes during zebrafish heart regeneration and suggests that repression of similar structural components in the border zone of the infarcted human heart might improve its regenerative capacity.

ORGANISM(S): Danio rerio

PROVIDER: GSE96930 | GEO | 2019/09/17

REPOSITORIES: GEO

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Project description:Ischemic cardiopathy is the leading cause of death in the world, for which efficient regenerative therapy is not currently available. In mammals, after a myocardial infarction episode, the damaged myocardium is replaced by scar tissue featuring collagen deposition and tissue remodelling with negligible cardiomyocyte proliferation. Zebrafish, in contrast, display an extensive regenerative capacity as they are able to restore completely lost cardiac tissue after partial ventricular amputation. Due to the lack of genetic lineage tracing evidence, it is not yet clear if new cardiomyocytes arise from existing contractile cells or from an uncharacterised set of progenitors cells. Nonetheless, several genes and molecules have been shown to participate in this process, some of them being cardiomyocyte mitogens in vitro. Though questions as what are the early signals that drive the regenerative response and what is the relative role of each cardiac cell in this process still need to be answered, the zebrafish is emerging as a very valuable tool to understand heart regeneration and devise strategies that may be of potential value to treat human cardiac disease. Here, we performed a genome-wide transcriptome profile analysis focusing on the early time points of zebrafish heart regeneration and compared our results with those of previously published data. Our analyses confirmed the differential expression of several transcripts, and identified additional genes the expression of which is differentially regulated during zebrafish heart regeneration. We validated the microarray data by conventional and/or quantitative RT-PCR. For a subset of these genes, their expression pattern was analyzed by in situ hybridization and shown to be upregulated in the regenerating area of the heart. The specific role of these new transcripts during zebrafish heart regeneration was further investigated ex vivo using primary cultures of zebrafish cardiomyocytes and/or epicardial cells. Our results offer new insights into the biology of heart regeneration in the zebrafish and, together with future experiments in mammals, may be of potential interest for clinical applications. In order to study zebrafish heart regeneration, a time course experiment was realized where amputated heart regenerating were compared to control heart. Samples in triplicate were extracted at 1, 3, 5 and 7 days post-amputation.

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H3K27me3-mediated silencing of structural genes is required for zebrafish heart regeneration

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