RNA-binding protein with multiple splicing (Rbpms) contributes to noncompaction cardiomyopathy by regulating cardiomyocyte cytokinesis and binucleation
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ABSTRACT:
PROVIDER: PRJNA758402 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15657175.fastq.gz | Fastqsanger.gz | |||
| SRR15657175_1.fastq.gz | Fastqsanger.gz | |||
| SRR15657175_2.fastq.gz | Fastqsanger.gz | |||
| SRR15657176.fastq.gz | Fastqsanger.gz | |||
| SRR15657176_1.fastq.gz | Fastqsanger.gz |
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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
Project description:Background: Modulation of mRNA splicing acts as an important layer of gene regulation, in addition to transcriptional regulation and epigenetic modifications. RNA binding proteins (RBPs) play essential roles in mediating RNA splicing and are key regulators of heart development and function. Our previous studies demonstrated that RBPMS (RNA-binding protein with multiple splicing) regulates cardiac development through modulating mRNA splicing during embryogenesis. Here we explored the postnatal function of RBPMS in the heart. Methods: We ablated Rbpms in the heart by generating a cardiac-specific knockout mouse line (Myh6-Cre, Rbpmsfl/fl), and evaluated its cardiac functions by histology, echocardiography, and gene expression. Paired-end RNA sequencing and RT-PCR were performed to identify and validate splicing targets of RBPMS in adult mouse hearts. Proximity-dependent Biotin Identification (BioID) assay and mass spectrometry analysis were performed to identify RBPMS binding partners. We also measured contractility and calcium fluxes in isolated mouse cardiomyocytes, and contractile forces of cardiac papillary muscle. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) were also used as a model to explore the influence of RBPMS on contractility of human cardiomyocytes. Results: he absence of Rbpms in the heart led to dilated cardiomyopathy (DCM) and heart failure, causing early death in mice. Mice with cardiac-specific knockout of Rbpms showed myocardium noncompaction with reduced cardiomyocyte number at the neonatal stage and developed DCM with pervasive myocardial fibrosis in adulthood. We found that RBPMS mediates a largely distinct RNA splicing profile in adult mouse hearts compared to neonatal hearts, indicating a stage-specific modulation of alternative RNA splicing by RBPMS. In adult hearts, RBPMS mainly influenced alternative splicing of genes associated with sarcomere structures and cardiomyocyte contraction, such as Ttn, Pdlim5 and Nexn, to generate new protein isoforms. In neonatal hearts, RBPMS influenced the splicing of cytoskeletal genes. RBMPS was associated with spliceosome factors and other RNA binding proteins that play important roles in the heart, such as RBM20 and GATA4. Importantly, we found that the absence of Rbpms caused severe cardiomyocyte contractile defects and reduced calcium sensitivity in both mouse and hiPSC-CMs. Our results demonstrated that Rbpms is crucial for postnatal cardiac function and cardiomyocyte contractility by regulating RNA alternative splicing. Conclusions: Loss of Rbpms in the heart causes reduced cardiomyocyte number and impaired cardiomyocyte contraction, leading to DCM and heart failure.
2023-11-03 | GSE218672 | GEO
Project description: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.
2017-06-28 | GSE91078 | GEO
Project description:RBPMS regulates cardiomyocyte contraction and cardiac function through RNA alternative splicing
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Project description:Acute myeloid leukemia (AML) is a malignant tumor with high recurrence rate and poor prognosis. RNA-binding proteins (RBPs) are essential modulators of transcription and translation played critical roles and frequently dysregulated in AML. Here we show that RBPMS (RNA binding protein with multiple splicing) which is highly expressed in AML and associated with poor prognosis of AML, plays critical roles in leukemogenesis. Our study shows that inhibition of RBPMS abrogates self-renewal of leukemia initiating cells (LICs) and AML development but has little effect on normal hematopoiesis. Mechanistically, RBPMS maintains the stability of the m6A reader IGF2BP3 by USP1-mediated deubiquitination, which promotes the translation of the FOXO1 mRNA in an m6A-dependent manner. Moreover, RBPMS contributes to the progression of leukemia by promoting FOXO1/ENO2/ALDOC regulated glycolysis. Overexpression of FOXO1 has been shown to rescue RBPMS inhibition-induced phenotypes in both leukemia cells and mouse models. We have also designed a specific inhibitor of RBPMS that has therapeutic effects in the AML patient derived xenograft model (PDX) model. We, therefore, we highlight RBPMS as a promising drug target for AML therapy.
2023-10-04 | GSE230646 | GEO
Project description:Doxorubicin as a commonly used anthracycline has become the cornerstone of chemotherapy in a wide range of cancers owing to its high efficacy. However, clinical applications of doxorubicin are limited mainly due to its toxic effects on myocardium but the pathogenic mechanism of doxorubicin-induced cardiomyopathy are poorly understood. ADAM17 is known as tumor necrosis factor α converting enzyme (TACE), and the cleavage of TNF-α by ADAM17 is a prerequisite for pro-inflammatory TNF-α activity, which raises a possibility that inhibition of ADAM17 may exert a beneficial effect on disease processes where TNF-α plays an essential role. Our previous research has shown that cardiomyocyte specific knockout of ADAM17 improves diabetic cardiomyopathy by modulating cardiomyocyte apoptosis. However, the relationship between ADAM17 and doxorubicin-induced cardiomyopathy is unclear.Through RNA sequencing analysis, we observed significant changes in the TNF signaling pathway genes in the heart tissue of mice with or without cardiomyocyte ADAM17 knockout.
2024-09-10 | GSE276325 | GEO
Project description:Investigation of RBPMS role in post-transcriptional control of mRNAs in rat PAC1 pulmonary artery smooth muscle cells (SMCs). PolyA mRNA-Seq was carried out after RBPMS knockdown in differentiated PAC1 cells and after inducible RBPMS-A overexpression in dedifferentiated (proliferative) PAC1 cells.
2019-06-18 | GSE127799 | GEO
Project description:Aims Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that is characterized by progressive fibro-fatty replacement of the myocardium, arrhythmias, and sudden death. While myocardial degeneration and fibro-fatty replacement occurs in specific locations, the underlying molecular changes remain poorly characterized. Here we aim to delineate local changes in gene expression to help identify new genes or pathways that are relevant for specific remodelling processes occurring during ACM. Methods and Results Using Tomo-Seq, a genome-wide transcriptional profiling with high spatial resolution, we created a transmural epicardial to endocardial gene expression atlas of an explanted ACM heart to gain molecular insights into disease-driving processes. This enabled us to link gene expression profiles to the different regional remodelling responses and allowed us to identify genes that are potentially relevant for disease progression. In doing we revealed BTB (broad-complex, tramtrack, bric-à-brac) domain containing 11 (ZBTB11) to be specifically enriched at sites of active fibrofatty replacement of myocardium. Immunohistochemistry indicated ZBTB11 to be enriched in cardiomyocytes flanking fibrofatty areas, which could be confirmed in multiple cardiomyopathy patients. Forced overexpression of ZBTB11 in iPS-derived cardiomyocytes showed ZBTB11 to function as a potent inducer of cardiomyocyte atrophy. Conclusion By combining spatial transcriptomics with classical histological approaches we identified gene expression changes underlying local remodelling responses in ACM. In doing so we found ZBTB11 to function as a relevant driver of cardiomyocyte atrophy. These data show the power of Tomo-Seq to unveil new molecular mechanisms and indicate ZBTB11 as a potential new target for cardiomyopathy.
2021-05-22 | GSE114770 | GEO
Project description:In order to explore the underlying pathogenic role of Calsyntenin-1(CLSTN1) in dilated cardiomyopathy (DCM), we constructed cardiomyocyte-specific CLSTN1 overexpression (CLSTN1-OE) rats and a cumulative dose of 18 mg/kg doxorubicin were injected to induce DCM. Whole heart tissues from the Con-WT(n=4), Con-CLSTN1 OE(n=3), DCM-WT(n=3), and DCM-CLSTN1 OE(n=4) were collected for proteomics analysis via a QExactive mass spectrometer.
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Project description:Comparison between wild-type and cardiomyocyte-restricted knock-out of IL6 cytokines receptor component gp130 after surgical intervention for pressure-overload induced cardiomyopathy.
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