Cardiac endothelial cells maintain open chromatin and expression of cardiomyocyte myofibrillar genes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA605116 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11033454_1.fastq.gz | Fastqsanger.gz | |||
| SRR11033454_2.fastq.gz | Fastqsanger.gz | |||
| SRR11033455_1.fastq.gz | Fastqsanger.gz | |||
| SRR11033455_2.fastq.gz | Fastqsanger.gz | |||
| SRR11033456_1.fastq.gz | Fastqsanger.gz |
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Project description:Endothelial cells (ECs) are widely heterogenous depending on tissue and vascular localization. Jambusaria et al. recently demonstrated that ECs in various tissues surprisingly possess mRNA signatures of their underlying parenchyma. The mechanism underlying this observation remains unexplained, and could include mRNA contamination during cell isolation, in vivo mRNA paracrine transfer from parenchymal cells to ECs, or cell-autonomous expression of these mRNAs in ECs. Here, we use a combination of bulk RNASeq, single-cell RNASeq datasets, in situ mRNA hybridization, and most importantly ATAC-Seq of FACS-isolated nuclei, to show that cardiac ECs actively express cardiomyocyte myofibril (CMF) genes and have open chromatin at CMF gene promoters. These open chromatin sites are enriched for sites targeted by cardiac transcription factors, and closed upon expansion of ECs in culture. Together, these data demonstrate unambiguously that the expression of CMF genes in ECs is cell-autonomous, and not simply a result of technical contamination or paracrine transfers of mRNAs, and indicate that local cues in the heart in vivo unexpectedly maintain fully open chromatin in ECs at genes previously thought limited to cardiomyocytes.
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Project description:The transition from progenitor to differentiated cells is critical for successful organogenesis; subtle alterations in this process can lead to developmental disorders. The anterior heart field (AHF) encompasses a niche in which cardiac progenitors maintain their multipotent and undifferentiated nature by signals from the surrounding tissues, which thus far have been poorly defined. Using systems biology approaches and perturbations of signaling molecules in chick embryos, we revealed a tight crosstalk between the bone morphogenic protein (BMP) and fibroblast growth factor (FGF) signaling pathways within the AHF: BMP4 promotes myofibrillar gene expression and cardiomyocyte contractions, by blocking FGF signaling. Furthermore, inhibition of the FGF-ERK pathway is both sufficient and necessary for these processes, suggesting that FGF signaling blocks premature differentiation of cardiac progenitors in the AHF. Investigating the molecular mechanisms downstream to BMP signaling revealed that BMP4 induced a set of neural crest-related genes; including MSX1, which was sufficient to induce cardiomyocyte differentiation. We suggest that BMP and FGF signaling pathways act via inter- and intra-regulatory loops in multiple tissues, to coordinate the balance between proliferation and differentiation of cardiac progenitors. Splanchnic mesoderm (AHF) explants were dissected and cultured for 0, 3, 12 or 24 hrs on a collagen drop covered with 0.5 ml of dissection medium (10% Fetal Calf Serum, chick embryo extract 2.5% and pen/strep 0.5% in MEM medium). 12 hour time point was used as a duplicate. In all samples, there was control plus BMP4: human recombinant BMP4 (Sigma, 200 ng/mL), which was added to the explant dissection medium.
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Project description:: The adult heart develops hypertrophy to reduce ventricular wall stress and maintain cardiac function in response to an increased workload. Although pathological hypertrophy generally progresses to heart failure, physiological hypertrophy may be cardioprotective. Cardiac-specific overexpression of the lipid-droplet protein perilipin 5 (Plin5) promotes cardiac hypertrophy, but it is unclear if this response is beneficial. We analyzed human RNA-sequencing data from the left ventricle and showed that cardiac PLIN5 expression correlates with upregulation of cardiac contraction-related processes. To investigate how elevated cardiac Plin5 levels affect cardiac contractility, we generated mice with cardiac-specific overexpression of Plin5 (MHC-Plin5 mice). These mice displayed increased left ventricular mass and cardiomyocyte size but preserved heart function. Quantitative proteomics identified sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) as a Plin5-interacting protein. Phosphorylation of phospholamban, the master regulator of SERCA2, was increased in MHC-Plin5 versus wild-type cardiomyocytes. Live imaging showed increases in intracellular Ca2+ release during contraction, Ca2+ removal during relaxation, and SERCA2 function in MHC-Plin5 versus wild-type cardiomyocytes. These results identify a role for Plin5 in improving cardiac contractility through enhanced Ca2+ signaling.
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Project description:Background: Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we employed an integrated transcriptomics and bioinformatics analysis and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. The role of HIPK2 in cardiac biology is unknown. Methods: We used the Expression2Kinase algorithm for the screening of kinase targets. To determine the role of HIPK2 in the heart, we generated cardiomyocyte-specific HIPK2 knockout (CM-KO) and heterozygous (CM-Het) mice. Heart function was examined by echocardiography and related cellular and molecular mechanisms were examined. Adeno-associated virus serotype 9 (AAV9) carrying cardiac-specific constitutively active MEK1 (TnT-MEK1-CA) were administrated to rescue cardiac dysfunction in CM-KOs. Results: To our knowledge, this is the first study to define the role of HIPK2 in cardiac biology. Using multiple HIPK2 loss-of-function mouse models, we demonstrated that reduction of HIPK2 in cardiomyocytes leads to cardiac dysfunction—suggesting a causal role in heart failure. Importantly, cardiac dysfunction in HIPK2 KOs developed with advancing age, but not during development. In addition, CM-KO and CM-Het exhibited a gene dose-response relationship of cardiomyocyte HIPK2 on heart function. HIPK2 expression in the heart was significantly reduced in human end-stage ischemic cardiomyopathy compared to non-failing myocardium, suggesting a clinical relevance of HIPK2 in cardiac biology. In vitro studies with neonatal rat ventricular cardiomyocytes corroborated the in vivo findings. Specifically, adenovirus-mediated overexpression of HIPK2 suppressed the expression of heart failure markers, NPPA and NPPB, at basal condition and abolished phenylephrine-induced pathological gene expression. An array of mechanistic studies revealed impaired ERK1/2 signaling in HIPK2 deficient hearts. In vivo rescue experiment with AAV9 TnT-MEK1-CA nearly abolished the detrimental phenotype of KOs suggesting that impaired ERK signaling mediated apoptosis as the key factor driving the detrimental phenotype in CM-KO hearts. Conclusions: Taken together, these findings suggest that cardiomyocyte HIPK2 is required to maintain normal cardiac function via ERK signaling
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