Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

H3K27me3 deposition over sarcomeric and cytoskeletal promoters is required for cardiomyocyte cytokinesis and wound invasion during zebrafish heart regeneration [RNA-seq]

ABSTRACT: We identify the global transcriptional changes that occur between homeostatic and proliferative cardiomyocytes in the zebrafish heart and uncover an essential role for H3K27me3 deposition in facilitating successful myocardial regeneration. Specifically, we learned that cardiomyocyte proliferation is accompanied by downregulation of sarcomeric and cytoskeletal components and upregulation of the polycomb methylase Ezh2. Using ChIPseq, we demonstrate that this transcriptional repression is associated with deposition of new H3K27me3 modifications over the promoters. Using new genetic zebrafish lines that allow for inducible and cardiomyocyte-specific expression of a mutant form of histone 3 that is unable to be tri-methylated on lysine 27 (H3.3K27M), we discovered that addition of H3K27me3 marks is essential for cardiac regeneration in vivo. Earlier in the regenerative window, we found that H3.3K27M–expressing wound edge cardiomyocytes aberrantly maintain homeostatic levels of sarcomeric and actomyosin gene expression and show significant retention of sarcomere structure. While DNA replication occurs normally in these H3.3K27M cardiomyocytes, we observed significant increases in cardiomyocyte nucleation, a phenotype indicative of cytokinesis failures. In addition, nuclear density at the wound edge increases as new cardiomyocytes fail to colonize the injured area. Together, our study reveals that production of new cardiomyocytes and their infiltration into the injured region relies on H3K27me3-mediated sarcomeric and actomyosin cytoskeletal gene repression.

ORGANISM(S): Danio rerio

PROVIDER: GSE96929 | GEO | 2019/09/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

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

Project description: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.

2019-09-17 | GSE96930 | GEO

H3K27me3 deposition over sarcomeric and cytoskeletal promoters is required for cardiomyocyte cytokinesis and wound invasion during zebrafish heart regeneration [ChIP-seq]

Project description:Deciphering the genetic and epigenetic regulation of injury-induced heart regeneration 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 gene expression changes 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 high-throughput transcriptional and chromatin analyses, we identified correlations between gene expression changes and activating H3K4me3 and/or repressive H3K27me3 dynamics 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.

2019-09-17 | GSE96928 | GEO

ZEB2 protects the heart from ischemic damage

Project description:infarct size and subsequent deterioration in function. The identification of factors that enhance cardiac repair by the restoration of the vascular network is, therefore, of great significance. Here, we show that the transcription factor Zinc finger E-box-binding homeobox 2 (ZEB2) is increased in stressed cardiomyocytes and induces a cardioprotective cross-talk between cardiomyocytes and endothelial cells to enhance angiogenesis after ischemia. Single-cell sequencing indicates ZEB2 to be enriched in injured cardiomyocytes. Cardiomyocyte-specific deletion of ZEB2 results in impaired cardiac contractility and infarct healing post-myocardial infarction (post-MI), while cardiomyocyte-specific ZEB2 overexpression improves cardiomyocyte survival and cardiac function. We identified Thymosin 4 (TMSB4) and Prothymosin (PTMA) as main paracrine factors released from cardiomyocytes to stimulate angiogenesis by enhancing endothelial cell migration, and whose regulation is validated in our in vivo models. Therapeutic delivery of ZEB2 to cardiomyocytes in the infarcted heart induces the expression of TMSB4 and PTMA, which enhances angiogenesis and prevents cardiac dysfunction. These findings reveal ZEB2 as a beneficial factor during ischemic injury, which may hold promise for the identification of new therapies.

2021-03-23 | PXD022212 | Pride

GDF10 promotes rodent cardiomyocyte maturation during the postnatal period

Project description:Cardiomyocytes and cardiac fibroblasts undergo coordinated maturation after birth, and cardiac fibroblasts are required for postnatal cardiomyocyte maturation in mice. Here, we investigate the role of cardiac fibroblast-expressed Growth Differentiating Factor 10 (GDF10) in postnatal heart development. In neonatal mice, Gdf10 is expressed specifically in cardiac fibroblasts, with its highest expression coincident with onset of cardiomyocytes cell cycle arrest and transition to hypertrophic growth. In neonatal rat ventricular myocyte cultures, GDF10 treatment promotes cardiomyocyte maturation indicated by increased binucleation, downregulation of cell cycle progression genes and upregulation of cell cycle inhibitor genes. GDF10 treatment leads to an increase in cardiomyocyte cell size together with increased expression of mature sarcomeric protein isoforms and decreased expression of fetal cardiac genes. RNAsequencing of GDF10-treated NRVM shows an increase in gene expression related to myocardial maturation, including upregulation of sodium and potassium channel genes. In vivo, loss of Gdf10 leads to a delay in myocardial maturation indicated by a decrease in cardiomyocyte cell size and binucleation as well as increased mitotic activity at postnatal (P) day 7. Further, induction of mature sarcomeric protein isoform gene expression is delayed, and expression of cell cycle progression genes is prolonged. However, by P10 indicators of cardiomyocyte maturation and mitotic activity are normalized in Gdf10-null hearts relative to controls. Together, these results implicate Gdf10 as a novel crosstalk mediator between cardiomyocytes and cardiac fibroblasts, required for appropriate timing of cardiomyocyte maturation steps including binucleation, hypertrophy, mature sarcomeric isoform switch and cell cycle arrest in the postnatal period.

2025-02-11 | GSE284190 | GEO

Direct reprogramming of mouse fibroblasts into cardiomyocytes with chemical cocktails

2015-08-23 | GSE69924 | GEO

Direct reprogramming of mouse fibroblasts into cardiomyocytes with chemical cocktails

Project description:The direct conversion, or trans-differentiation, of non-cardiac cells into cardiomyocytes by forced expression of transcription factors and microRNAs provide promising ways of cardiac regeneration. However, genetic manipulations are still not desirable in real clinical applications. we report the generation of automatically beating cardiomyocyte-like cells from mouse fibroblasts with only chemical cocktails. These chemical-induced cardiomyocyte-like cells (CiCMs) express cardiomyocyte-specific markers, exhibit sarcomeric organization, and possess typical cardiac calcium flux and electrophysiological features. Microarray-bassed gene expression patterns of Mouse embryonic fibroblasts (MEFs), CiCMs, and cardiomyocytes(CMs) indicated a clear transition from dividing MEFs to differentiated cardiomyocyte-like state in CiCM samples. Mouse embryonic fibroblasts were treated with a small-molecule combination CRFVPT (10 μM CHIR99021 (C); 10 μM RepSox (R); 50 μM Forskolin (F); 0.5 mM VPA (V); 5 μM Parnate, (P); 1 μM TTNPB (T)) to induce transdifferentiation to chemical-induced cardiomyocyte-like cells. CiCMs beating clusters were picked at day 24 for analysis. MEFs were isolated from mouse embryos, and CMs were isolated from mouse hearts. Total RNA of MEFs, CiCMs and CMs were extracted and hybridization on Affymetrix microarrays.

2015-08-23 | E-GEOD-69924 | biostudies-arrayexpress

cited4a limits CM dedifferentiation and proliferation during zebrafish heart regeneration [snRNA-seq]

Project description:Cardiac regeneration involves interplay of complex interactions between many different cell types, including cardiomyocytes. The exact mechanism that enables cardiomyocytes to undergo dedifferentiation and proliferation to replace lost cells has been under intense study. Here we report single nuclear RNA sequencing profile of the injured zebrafish heart and identified distinct cardiomyocyte populations in the injured heart. These cardiomyocyte populations indicate diverse functions that includes stress-response, myofibril assembly, proliferation and contraction. The contracting cardiomyocyte population also involves activation of maturation pathways as an early response to injury. This intriguing finding suggests that constant maintenance of distinctive terminally differentiated cardiomyocyte population is important for cardiac function during regeneration. To test this, we determined that cited4a, a p300/CBP transcriptional co-activator, is induced after injury in mature cardiomyocyte population. Moreover, loss-of-cited4a mutants showed increased dedifferentiation, proliferation and accelerated heart regeneration. Thus, suppressing cardiomyocyte maturation pathway activity in injured hearts could be an approach to promote heart regeneration.

2025-01-31 | GSE279845 | GEO

cited4a limits CM dedifferentiation and proliferation during zebrafish heart regeneration [Bulk RNA-seq]

2025-01-31 | GSE279843 | GEO

Border-zone cardiomyocytes and macrophages contribute to remodeling of the extracellular matrix to promote cardiomyocyte invasion during zebrafish cardiac regeneration

Project description:Despite numerous advances in our understanding of zebrafish cardiac regeneration, an aspect that remains less studied is how newly proliferated cardiomyocytes invade, and eventually replace, the collagen-containing fibrotic tissue following injury. Here, we provide an in-depth analysis of the process of cardiomyocyte invasion and migration using live-imaging and histological approaches. We observed a close interaction between protruding cardiomyocytes and macrophages at the wound border zone, and irf8 mutant zebrafish, which largely lack macrophages, exhibited defects in extracellular matrix (ECM) remodeling and cardiomyocyte protrusion into the injured area. Using a resident macrophage ablation model, we show that defects in ECM remodeling at the border zone and subsequent cardiomyocyte protrusion can be partly attributed to a population of resident macrophages. Single-cell RNA-sequencing analysis of cells at the wound border revealed a population of cardiomyocytes and macrophages with fibroblast-like gene expression signatures, including the expression of genes encoding ECM structural proteins and ECM-remodeling proteins. The expression of mmp14b, which encodes a membrane-anchored matrix metalloproteinase, was restricted to cells in the border zone and genetic deletion of mmp14b led to a decrease in 1) collagen degradation at the border zone, 2) macrophage recruitment to the border zone, and 3) subsequent cardiomyocyte invasion. Furthermore, cardiomyocyte-specific overexpression of mmp14b was sufficient to enhance cardiomyocyte invasion both into the injured area and along the apical surface of the wound. Altogether, our data shed important insights into the process of cardiomyocyte invasion of the collagen-containing injured tissue during cardiac regeneration. They further suggest that cardiomyocytes and resident macrophages contribute to ECM remodeling at the border zone to promote cardiomyocyte replenishment of the fibrotic injured tissue.

2025-03-11 | GSE251856 | GEO

Danio rerio

Project description:H3K27me3 deposition over sarcomeric and cytoskeletal promoters is required for cardiomyocyte cytokinesis and wound invasion during zebrafish heart regeneration [ChIP-seq]

| PRJNA380130 | ENA

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data