Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Deletion of Gas2l3 in mice leads to specific defects in cardiomyocyte cytokinesis during development

ABSTRACT: Mammalian cardiomyocytes lose the ability to proliferate shortly after birth. This accounts for the limited regeneration capacity of the mammalian heart. A characteristic feature of growth arrested cardiomyocytes is binucleation, but the molecular mechanisms are not well understood. In rodents, binucleation of cardiomyocytes starts after birth and occurs through incomplete cytokinesis. Here we demonstrate an important and unexpected role of GAS2L3, a recently identified actin and tubulin binding protein, for cardiomyocyte cytokinesis during heart development in mice. Mice deficient in GAS2L3 die shortly after birth due to dilated cardiomyopathy. Cardiomyocyte-specific deletion of GAS2L3 confirmed that the phenotype resulted from the loss of GAS2L3 in cardiomyocytes. We show that a deficiency in GAS2L3 leads to a strong reduction in cardiomyocyte numbers due to reduced proliferation. In addition, the loss of Gas2l3 resulted in premature binucleation of cardiomyocytes and in induction of a p53-transcriptional program including the cell cycle inhibitor p21. Collectively, these data identify an important role for GAS2L3 in cardiomyocyte cytokinesis during development.

ORGANISM(S): Mus musculus

PROVIDER: GSE91078 | GEO | 2017/06/28

SECONDARY ACCESSION(S): PRJNA356839

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

RNA-binding protein with multiple splicing (Rbpms) contributes to noncompaction cardiomyopathy by regulating cardiomyocyte cytokinesis and binucleation

Project description:Noncompaction cardiomyopathy is a common congenital cardiomyopathy associated with a deficiency of ventricular cardiomyocytes and impaired pump function. The genetic basis and underlying mechanisms of this disorder remain elusive. Polyploidization is an intrinsic feature of mammalian cardiomyocytes, which occurs shortly after birth and is accompanied by cardiomyocyte cell cycle arrest. We show that genetic deletion of the RNA binding protein with multiple splicing (Rbpms) in mice results in premature onset of cardiomyocyte polyploidization (binucleation) and consequent noncompaction cardiomyopathy. A similar blockade to cytokinesis occurs in human iPSC-derived cardiomyocytes with RBPMS gene deletion. Paired-end RNA sequencing analysis revealed that Rbpms plays an essential role in RNA splicing and mediates isoform switching from the short to the long form of Pdlim5, a heart-specific LIM domain protein that connects the sarcomere with various signaling proteins during heart development. The loss of Rbpms leads to abnormal accumulation of short Pdlim5 isoforms that disrupt cardiomyocyte cytokinesis. Our results link premature cardiomyocyte binucleation to noncompaction cardiomyopathy and highlight the central role of Rbpms in this process.

2022-02-17 | GSE182949 | GEO

Repression of Ect2 induces cytokinesis failure and decreases heart muscle cell proliferation in congenital heart disease

Project description:Proliferation of heart muscle cells (cardiomyocytes) is the basis for heart development and regeneration. In mammals, cardiomyocytes become binucleated, which is thought to limit their proliferative capacity, but mechanisms are unknown. Here, we show the detailed mechanisms of formation of binucleated cardiomyocytes and how these mechanisms are dysregulated in congenital heart disease (CHD). Cardiomyocytes become binucleated by failing the last stage of cytokinesis, abscission. We identified the underlying molecular mechanism with single-cell transcriptional profiling, which showed repression of the cytokinesis gene Ect2, a Rho-guanine-nucleotide exchange factor. Inactivating Ect2 tripled the proportion of binucleated cardiomyocytes and reduced the number of cardiomyocytes by 34% in newborn mice, which was lethal. Cardiomyocyte-specific overexpression of Ect2 in transgenic mice decreased cytokinesis failure. We demonstrate that the Ect2 gene is regulated by the Hippo tumor suppressor pathway, and upstream of that, by β-adrenergic receptor signaling. In neonatal mice, stimulating β-adrenergic signaling pathway output with forskolin decreased the number of cardiomyocytes, and administration of β-blockers increased the number of cardiomyocytes. Finally, we show that patients with tetralogy of Fallot with pulmonary stenosis (ToF/PS), a common type of CHD, develop a 2.2-fold increase in bi- and multi-nucleated cardiomyocytes. Using in vivo labeling of one ToF/PS patient with 15N-thymidine, followed by imaging mass spectrometry, we demonstrate that this increase happens after birth. Organotypic cultures of myocardium from infants with ToF/PS showed that cardiomyocyte binucleation could be reduced with β-blockers. These results demonstrate how cardiomyocyte proliferation stops and provide the basis for new therapeutic strategies to increase cardiomyocyte proliferation in patients with CHD.

2019-09-30 | GSE108359 | GEO

Direct comparison of mononucleated and binucleated cardiomyocytes reveals molecular mechanisms underlying distinct proliferative competencies

Project description:The mammalian heart is incapable of regenerating a sufficient number of cardiomyocytes to ameliorate the loss of contractile muscle after acute myocardial injury, often resulting in heart failure. Several reports have demonstrated that mononucleated (MoNuc) cardiomyocytes are more responsive to pro-proliferative stimuli than are binucleated (BiNuc) cardiomyocytes. However, techniques to isolate and characterize these two different cardiomyocyte populations have been lacking. We have developed a novel fluorescence associated cell sorting method to isolate highly enriched populations of MoNuc and BiNuc cardiomyocytes at various times of development. Transcriptome analysis reveals an underlying biological signature that defines the differences between MoNucs and BiNucs, including a central role for the E2f/Rb transcriptional network in establishing the divergent ability of these two populations to re-enter and complete the cell cycle. Moreover, inducing binucleation by genetically blocking the ability of cardiomyocytes to complete cytokinesis leads to a reduction in E2f target gene expression, linking the E2f pathway with nucleation. These data identify key molecular differences between MoNuc and BiNuc mammalian cardiomyocytes that can be used to leverage cardiomyocyte proliferation for promoting injury repair in the heart.

2020-02-26 | GSE140851 | GEO

AP-1 activation mediates postnatal cardiomyocyte maturation

Project description:Mammalian cardiomyocytes rapidly mature after birth, with hallmarks such as cell-cycle exit, binucleation, and metabolic switch to oxidative phosphorylation of lipids. The causes and transcriptional programs regulating cardiomyocyte maturation are not fully understood yet. Thus, we performed single cell RNA-seq of neonatal and postnatal day 7 rat hearts to identify the key factors for this process and found AP-1 as a key factor to regulate cardiomyocyte maturation. To find the mechanism of AP-1 during cardiomyocyte maturation, we performed RNA-seq analysis of neonatal rat ventricular cardiomyocytes and found Ap-1 promote cardiomyocyte maturation by regulating cardiomyocyte metabolism.

2021-12-01 | GSE182422 | GEO

Analysis of cardiac miRNA expression in the early neonatal period

Project description:The regenerative capacity of the mammalian heart is lost quickly after birth when cardiomyocytes stop dividing and undergo cell cycle arrest. Thus, the adult mammalian heart lacks the ability to heal itself to any appreciable amount after ischemic injury such as myocardial infarction. Heart growth begins during fetal life with the first phase of DNA synthesis that is exclusively associated with cardiomyocyte proliferation. This process proceeds until 12 hours after birth and is defined as 0 days in our submitted samples. Cardiomyocytes division is undetectable at neonatal day 1. To analyze the molecular mechanisms responsible for cessation of cardiomyocyte proliferation, we performed genome-wide miRNA microarray profiling by comparing postnatal days 0 vs 1d.This revealed a profile of 8 significantly downregulated miRNAs in the proliferative DKO hearts (versus vehicle-injected control), that were enriched for mRNA targets involved in cell cycle regulation. In vitro studies have demonstrated that knockdown of these 8 miRNAs in neonatal rat cardiomyocytes can increase the occurrence of cytokinetic events. Ultimately, we aim to inject antagomirs targeting these miRNAs into mice post-myocardial infarction to determine the effect of these miRNAs on heart function and cardiomyocyte proliferation in vivo.

2022-01-30 | E-MTAB-9256 | biostudies-arrayexpress

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

Project description: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.

2019-09-17 | GSE96929 | GEO

High-throughput single cardiomyocyte transcriptomics identify novel gene programs underlying the normal developmental process of terminal cardiomyocyte differentiation

Project description:It is generally accepted that G2M cell cycle arrest occurs around birth (P3 in mice) as a natural process of cardiomyocyte (CM) terminal differentiation resulting in binucleation/polyploidization that renders the mammalian heart non-regenerative after damage. Mechanisms underlying this postnatal switch in CM proliferation remain unclear. Herein, we developed a novel approach combining fluorescence-activated cell sorting (FACS) with single cell RNA sequencing (scRNA-seq) of fixed CMs and specifically identified transcription factors (TFs) involved in G2M cell cycle completion of mouse CMs.

2023-03-16 | GSE162959 | GEO

Amino acid priming of mTOR is essential for heart regeneration

Project description:For a short period of time in mammalian neonates, the mammalian heart can regenerate via cardiomyocyte proliferation. This regenerative capacity is largely absent in adults. In other organisms, including zebrafish, damaged hearts can regenerate throughout their lifespans. Many studies have been performed to understand the mechanisms of cardiomyocyte de-differentiation and proliferation during heart regeneration however, the underlying reason why adult zebrafish and young mammalian cardiomyocytes are primed to enter cell cycle have not been identified. Here we show the primed state of a pro-regenerative cardiomyocyte is dictated by its amino acid profile and metabolic state. Adult zebrafish cardiomyocyte regeneration is a result of amino acid-primed mTOR activation. Zebrafish and neonatal mouse cardiomyocytes display elevated glutamine levels, predisposing them to amino acid-driven activation of mTORC1. Injury initiates Wnt/β-catenin signalling that instigates primed mTORC1 activation, Lin28 expression and metabolic remodeling necessary for zebrafish cardiomyocyte regeneration. These studies reveal a unique mTORC1 primed state in zebrafish and mammalian regeneration competent cardiomyocytes.

2022-02-15 | PXD011791 | Pride

Arid1a is essential in cardiomyocytes for neonatal heart maturation [RNA-seq]

Project description:Adult mammalian hearts do not regenerate following ischemic injury, causing permanent damage to the myocardium, often leading to heart failure. In contrast, neonatal mouse hearts can fully regenerate after injury, however this ability is lost shortly after birth. Loss of regenerative capacity coincides with profound changes in the epigenetic landscape. Yet, the mechanisms controlling cardiomyocyte proliferation remain poorly understood. To identify epigenetic mechanisms that underlie cardiomyocyte regeneration in response to ischemic injury, we subjected mice to sham or ischemia-reperfusion injury (IR) and performed RNA-Seq at multiple timepoints after injury. Multiple SWI/SNF chromatin remodeling complex subunits were upregulated after IR, including the AT-rich interactive domain-containing protein 1A (Arid1a), which has previously been implicated in tissue regeneration. Here, we show that Arid1a is abundantly expressed in cardiomyocytes during development, and is reactivated in a subset of adult cardiomyocytes after IR. Moreover, ARID1A is highly expressed in cardiomyocytes in human failing hearts, suggesting an important function in injury response. Cardiomyocyte-specific Arid1a ablation in neonatal mice induced cardiomyocyte hyperplasia, and severe cardiac enlargement at 2 weeks of age. Arid1a mutant hearts display increased expression of key cell cycle genes. Using ChIP-Seq and protein interaction studies we show that Arid1a functionally interacts with HIPPO signaling, thereby regulating neonatal cardiomyocyte proliferation. Furthermore, suppression of Arid1a in adult cardiomyocytes after IR induced cell cycle activity in border zone cardiomyocytes. These data suggest that Arid1a regulates cardiomyocyte proliferation and function. Upregulation of Arid1a in cardiomyocytes after injury may suppress proliferation and regeneration. Modulation of ARID1A after ischemic injury may be a novel therapeutic target to enhance cardiac regeneration.

2023-07-06 | GSE155101 | GEO

Arid1a is essential in cardiomyocytes for neonatal heart maturation [ChIP-seq]

2023-07-06 | GSE155100 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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