Induction of adult cardiomyocyte renewal by Klf1
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE152531 | GEO | 2020/10/31
REPOSITORIES: GEO
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Project description:In contrast to mammals, zebrafish regenerate heart injuries via proliferation of cardiomyocytes located at the wound border. Here, we show that tomo-seq can be used to identify whole-genome transcriptional profiles of the injury zone, the border zone and the healthy myocardium. Interestingly, the border zone is characterized by the re-expression of embryonic cardiac genes that are also activated after myocardial infarction in mouse and human, including targets of Bone Morphogenetic Protein (BMP) signaling. Endogenous BMP signaling has been reported to be detrimental to mammalian cardiac repair. In contrast, we find that genetic or chemical inhibition of BMP signaling in zebrafish reduces cardiomyocyte dedifferentiation and proliferation, ultimately compromising myocardial regeneration, while bmp2b overexpression is sufficient to enhance it. Our results provide a resource for further studies on the molecular regulation of cardiac regeneration and reveal intriguing differential cellular responses of cardiomyocytes to a conserved signaling pathway in regenerative versus non-regenerative hearts. To generate spatially-resolved RNA-seq data for injured zebrafish hearts (3 and 7 days-post-injury), we cryosectioned samples, extracted RNA from the individual sections, and amplified and barcoded mRNA using the CEL-seq protocol (Hashimshony et al., Cell Reports, 2012) with a few modifications. Libraries were sequenced on Illumina NextSeq using 75bp paired end sequencing.
2016-01-11 | E-GEOD-74652 | biostudies-arrayexpress
Project description:In contrast to mammals, zebrafish regenerate heart injuries via proliferation of cardiomyocytes located at the wound border. Here, we show that tomo-seq can be used to identify whole-genome transcriptional profiles of the injury zone, the border zone and the healthy myocardium. Interestingly, the border zone is characterized by the re-expression of embryonic cardiac genes that are also activated after myocardial infarction in mouse and human, including targets of Bone Morphogenetic Protein (BMP) signaling. Endogenous BMP signaling has been reported to be detrimental to mammalian cardiac repair. In contrast, we find that genetic or chemical inhibition of BMP signaling in zebrafish reduces cardiomyocyte dedifferentiation and proliferation, ultimately compromising myocardial regeneration, while bmp2b overexpression is sufficient to enhance it. Our results provide a resource for further studies on the molecular regulation of cardiac regeneration and reveal intriguing differential cellular responses of cardiomyocytes to a conserved signaling pathway in regenerative versus non-regenerative hearts.
2016-01-11 | GSE74652 | GEO
Project description:Fission yeast Schizosaccharomyces pombe is a model for studying cellular quiescence. Shifting to medium without a nitrogen-source induces proliferative cells to enter long-term G0 quiescence. Klf1 is a Kruppel-like transcription factor with a 7-amino acid-spaced C2H2-type zinc finger motif. The deletion mutant ∆klf1 normally divides in vegetative medium, but proliferation is not restored after long-term G0 quiescence. Cell biologic, transcriptomic, and metabolomic analyses revealed a unique phenotype of the ∆klf1 mutant in quiescence. Mutant cells had diminished transcripts related to signaling molecules for switching to differentiation. In contrast, proliferative metabolites for cell-wall assembly and antioxidants significantly increased. Further, the size of the ∆klf1 cells is markedly increased during quiescence due to the aberrant accumulation of calcofluor-positive chitin-like materials beneath the cell wall. After 4 weeks quiescence, the ability for reversible proliferation is lost, but energy metabolism is maintained. Klf1 thus plays a role in G0 phase longevity through enhancing the differentiation signal and suppressing metabolism for growth. If Klf1 is lost, S. pombe fails to maintain a constant cell size during quiescence.
2013-12-01 | GSE50986 | GEO
Project description:Backgound: Cardiac pressure overload, for example in patients with aortic stenosis, induces irreversible damage in the myocardium leading to cardiac dysfunction, cardiomyocyte hypertrophy and interstitial fibrosis. We therefore hypothesized that insufficient cardiac regeneration might contribute to the progression of pressure overload dependent disease. Here, we aimed to elucidate whether pressure overload in the regenerative stage shortly after birth could lead to a more adaptive cardiac response than in the non-regenerative stage in mice.nTAC in the non-regenerative stage induced cardiac dysfunction, myocardial fibrosis and cardiomyocyte hypertrophy. In contrast, during induction of nTAC in the regenerative stage, cardiac function remained intact and this was associated with enhanced myocardial angiogenesis and innervation as well as increased cardiomyocyte proliferation, but neither hypertrophy nor fibrosis. Mechanistically, inhibition of cardiomyocyte proliferation and angiogenesis in nTAC in the regenerative phase by rapamycin triggered mortality and myocardial fibrosis, which both also similarly occurred upon inhibition of angiogenesis by PTK787, suggesting that both processes are essential for the adaptive cardiac response to nTAC. A comparative genome-wide transcriptomic analysis between hearts after nTAC in the regenerative versus the non-regenerative stage defined differentially expressed functional gene classes, and a related bioinformatics analysis suggested the transcription factor GATA4 as master regulator of the regenerative gene-program. Indeed, cardiomyocyte specific deletion of GATA4 converted the regenerative nTAC into a non-regenerative, maladaptive response.tablished a new model of neonatal pressure-overload in mice, which when applied in the regenerative postnatal stage, triggers a purely adaptive myocardial response. Employing this model to identify new regulators might lead to novel therapeutic strategies to combat pressure overload induced myocardial disease.
2019-07-26 | GSE121308 | GEO
Project description:Fission yeast Schizosaccharomyces pombe is a model for studying cellular quiescence. Shifting to medium without a nitrogen-source induces proliferative cells to enter long-term G0 quiescence. Klf1 is a Kruppel-like transcription factor with a 7-amino acid-spaced C2H2-type zinc finger motif. The deletion mutant M-bM-^HM-^Fklf1 normally divides in vegetative medium, but proliferation is not restored after long-term G0 quiescence. Cell biologic, transcriptomic, and metabolomic analyses revealed a unique phenotype of the M-bM-^HM-^Fklf1 mutant in quiescence. Mutant cells had diminished transcripts related to signaling molecules for switching to differentiation. In contrast, proliferative metabolites for cell-wall assembly and antioxidants significantly increased. Further, the size of the M-bM-^HM-^Fklf1 cells is markedly increased during quiescence due to the aberrant accumulation of calcofluor-positive chitin-like materials beneath the cell wall. After 4 weeks quiescence, the ability for reversible proliferation is lost, but energy metabolism is maintained. Klf1 thus plays a role in G0 phase longevity through enhancing the differentiation signal and suppressing metabolism for growth. If Klf1 is lost, S. pombe fails to maintain a constant cell size during quiescence. Gene expression profile of fission yeast wild type cells and klf1-gene disruptant cells in proliferating state and in quiescent state. Type of experiment: Comparing between wild type cells and klf1-gene disruptant cells in proliferating condition and in quiescent condition. Experimental factor: Exponentially proliferating state in synthetic medium, EMM2, and quiescent G0 state in nitrogen-depleted synthetic medium, EMM2-N. Quality control steps taken: All experiments were repeated twice in each condition.
2013-12-01 | E-GEOD-50986 | biostudies-arrayexpress
Project description:We have demonstrated previously that adult cardiomyocytes can dedifferentiate and proliferate when cultured in vitro. To determine if cardiomyocyte dedifferentiation and cell cycling/proliferation happens in vivo, we applied here a novel multi-reporter transgenic mouse model (aMH-CMerCreMer;mT/MG;aMHC-H2BBFP) carrying reporter genes for permanent cardiomyocyte lineage mapping and maturity (dedifferentiation) reporting. With this new model, we deciphered the cellular sources and processes of cardiomyocyte dedifferentiation and proliferation in adult hearts. In this study, we used single-nucleus RNA-sequencing to tackle the challenges in analyzing the highly heterogeneous heart cell populations, and obtained datasets for a large number of cardiac single nuclei (both myocytes and non-myocytes) for control and post-infarct hearts. We identified specific cell populations in the heart using distinct transcriptomic clusters, transgenic reporters for ACM lineage and dedifferentiation, as well as cell cycle markers. The results demonstrated that the dedifferentiation and cell cycle progression of pre-existing CMs was augmented in post-infarct hearts, with a number of signaling pathways and gene sets affected. This is the first study dissecting the transcriptomic profiles and signaling pathways associated with cardiomyocyte dedifferentiation and cycling/proliferation in vivo using unbiased high-throughput single-nucleus RNA-Seq analysis, in junction with novel cell lineage (e.g. cardiomyocyte) and phenotyping (e.g. dedifferentiation) transgenic model systems.
2019-07-02 | GSE128628 | GEO
Project description:KLF1 (EKLF) regulates a diverse suite of genes to direct erythroid cell differentiation from bi-potent progenitors. To determine the local cis-regulatory contexts and transcription factor networks in which KLF1 operates, we performed KLF1 ChIP-seq in the mouse. We found at least 945 sites in the genome of E14.5 fetal liver erythroid cells which are occupied by endogenous KLF1. Many of these recovered sites reside in erythroid gene promoters such as β-globin, but the majority are distant to any known gene. Our data suggests KLF1 directly regulates most aspects of terminal erythroid differentiation including production of α and β-globin protein chains, heme biosynthesis, co-ordination of proliferation and anti-apoptotic pathways, and construction of the red cell membrane and cytoskeleton by functioning primarily as a transcriptional activator. Additionally, we suggest new mechanisms for KLF1 co-operation with other transcription factors, in particular the erythroid transcription factor GATA1, to maintain homeostasis in the erythroid compartment. Examination of KLF1 occupancy in primary erythroid cells. KLF1-ChIP and input samples were run on AB SOLiD Systems 2.0 and 3.0. The genomic alignment files (*sorted.txt) and peak file (*bed) contain the combined System 2.0 and 3.0 data.
2010-04-08 | E-GEOD-20478 | biostudies-arrayexpress
Project description:KLF1 (EKLF) regulates a diverse suite of genes to direct erythroid cell differentiation from bi-potent progenitors. To determine the local cis-regulatory contexts and transcription factor networks in which KLF1 operates, we performed KLF1 ChIP-seq in the mouse. We found at least 945 sites in the genome of E14.5 fetal liver erythroid cells which are occupied by endogenous KLF1. Many of these recovered sites reside in erythroid gene promoters such as β-globin, but the majority are distant to any known gene. Our data suggests KLF1 directly regulates most aspects of terminal erythroid differentiation including production of α and β-globin protein chains, heme biosynthesis, co-ordination of proliferation and anti-apoptotic pathways, and construction of the red cell membrane and cytoskeleton by functioning primarily as a transcriptional activator. Additionally, we suggest new mechanisms for KLF1 co-operation with other transcription factors, in particular the erythroid transcription factor GATA1, to maintain homeostasis in the erythroid compartment.
2010-04-08 | GSE20478 | GEO
Project description:Klf1 (formerly known as Eklf) regulates the development of erythroid cells from bi-potent progenitor cells via the transcriptional activation of a diverse set of genes. Mice lacking Klf1 die in utero prior to E15 from severe anemia due to the inadequate expression of genes controlling hemoglobin production, cell membrane and cytoskeletal integrity, and the cell cycle and proliferation. We have recently described the full repertoire of Klf1 binding sites in vivo by performing Klf1 ChIP-seq in primary erythroid tissue (E14.5 fetal liver). Here we describe the Klf1-dependent erythroid transcriptome by comparing mRNA-seq from Klf1+/+ and Klf1-/- erythroid tissue. This has revealed novel target genes not previously obtainable by traditional microarray technology and provided novel insights into the function of Klf1 as a transcriptional activator such as interactions with Gata1, Scl/Tal1 and p300. We also describe a set of erythroid specific promoters not previously identified that drive high level expression of otherwise ubiquitously expressed genes in erythroid cells. Additionally, our study has identified for the first time two novel lnc-RNAs that are dynamically expressed during erythroid differentiation as well as a role for Klf1 in directing apoptotic gene expression to drive the terminal stages of erythroid maturation. Examination of mRNA expression in 3 Klf1-/- and 3 Klf1+/+ fetal livers This submission represents mRNA-Seq component of study.
2012-04-01 | E-GEOD-33979 | biostudies-arrayexpress
Project description:Cardiac metabolism plays a crucial role in producing sufficient energy to sustain cardiac function. However, the role of metabolism in different aspects of cardiomyocyte regeneration remains unclear. Working with the adult zebrafish heart regeneration model, we first find an increase in the levels of mRNAs encoding enzymes regulating glucose and pyruvate metabolism, including pyruvate kinase M1/2 (Pkm) and pyruvate dehydrogenase kinases (Pdks), especially in tissues bordering the damaged area. We further find that impaired glycolysis decreases the number of proliferating cardiomyocytes following injury. These observations are supported by analyses using loss-of-function models for the metabolic regulators Pkma2 and peroxisome proliferator-activated receptor gamma coactivator 1 alpha. Cardiomyocyte-specific loss- and gain-of-function manipulations of pyruvate metabolism using Pdk3 as well as a catalytic subunit of the pyruvate dehydrogenase complex (PDC) reveal its importance in cardiomyocyte dedifferentiation and proliferation after injury. Furthermore, we find that PDK activity can modulate cell cycle progression and protrusive activity in mammalian cardiomyocytes in culture. Our findings reveal new roles for cardiac metabolism and the PDK-PDC axis in cardiomyocyte behavior following cardiac injury.
2020-07-13 | PXD016235 | Pride