Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The transcriptome of humans

ABSTRACT: Cumulative research demonstrated that heart muscles in the dilated cardiomyopathy (DCM) patients are marked by down-regulated expression of α-myosin heavy chain (α-MHC) coding by MYH6 while it remains unknown whether this reduction contributes to DCM. In our work, we proved that the expression level of α-MHC was decreased in the heart of DCM patients compared to that of non-failure donors. We established two Myh6 down-expressed Syrian Hamster models: one with α-MHC deficiency across all systems, the other with α-MHC knockdown specifically in the heart by using adeno-associatedvirus (AAV). Besides the animal models, we also programmed MYH6 knockout human-induced pluripotent stem cells (hiPSCs) which differentiated later into cardiomyocytes (hiPS-CMs) in vitro. We found α-MHC deficiency in vivo or in vitro both resulted in DCM phenotypes, meanwhile we demonstrated α-MHC deficiency is a causative factor of DCM. We also proved that the DCM-associated α-MHC deficiency was mediated by the autophagy flux. At the same time, the DCM phenotypes were attenuated by rapamycin, an autophagy activator, and exacerbated by inhibiting autophagic activities. Transcriptomic and proteomics results revealed that cardiomyocytes with α-MHC deficiency apparently exhibited actin cytoskeleton dysfunction. Our data demonstrated that α-MHC deficiency influenced the actin cytoskeleton network to regulate the autophagy activity suggesting that overexpress α-MHC or regulating autophagy would be a promising therapeutic candidate for DCM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241118 | GEO | 2024/08/16

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The transcriptome of mouse

Project description:Cumulative research demonstrated that heart muscles in the dilated cardiomyopathy (DCM) patients are marked by down-regulated expression of α-myosin heavy chain (α-MHC) coding by MYH6 while it remains unknown whether this reduction contributes to DCM. In our work, we proved that the expression level of α-MHC was decreased in the heart of DCM patients compared to that of non-failure donors. We established two Myh6 down-expressed Syrian Hamster models: one with α-MHC deficiency across all systems, the other with α-MHC knockdown specifically in the heart by using adeno-associatedvirus (AAV). Besides the animal models, we also programmed MYH6 knockout human-induced pluripotent stem cells (hiPSCs) which differentiated later into cardiomyocytes (hiPS-CMs) in vitro. We found α-MHC deficiency in vivo or in vitro both resulted in DCM phenotypes, meanwhile we demonstrated α-MHC deficiency is a causative factor of DCM. We also proved that the DCM-associated α-MHC deficiency was mediated by the autophagy flux. At the same time, the DCM phenotypes were attenuated by rapamycin, an autophagy activator, and exacerbated by inhibiting autophagic activities. Transcriptomic and proteomics results revealed that cardiomyocytes with α-MHC deficiency apparently exhibited actin cytoskeleton dysfunction. Our data demonstrated that α-MHC deficiency influenced the actin cytoskeleton network to regulate the autophagy activity suggesting that overexpress α-MHC or regulating autophagy would be a promising therapeutic candidate for DCM.

2024-08-16 | GSE241119 | GEO

The transcriptome of golden hamster

2024-08-16 | GSE241117 | GEO

Isogenic human pluripotent stem cell disease models reveal actin binding Rho activating protein deficiency underlies the cardiac troponin T DK210 mutation-induced familial dilated cardiomyopathy I

Project description:The cTnT-DK210 DCM mice showed ABRA protein deficiency, sarcomeric disruption, and compromised heart contractility. Heart-specific expression of ABRA in cTnT-DK210 mice restored sarcomeric structures, reversed the disease progress, and rescued the DCM phenotypes. ABRA deficiency and compromised downstream serum response factor-regulated muscle gene expression play a key role in familial DCM caused by the cTnT-DK210 mutation. ABRA is a good therapeutic gene for cTnT-DK210-induced DCM and could be translated to other cTnT mutations-induced familial DCM.

2021-10-01 | GSE154096 | GEO

Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset

Project description:About one third of dilated cardiomyopathy (DCM) cases are caused by mutations in sarcomere or cytoskeletal proteins. Yet treating the cytoskeleton directly is not possible because drugs that bind to actin are not well tolerated. Mutations in the actin binding protein CAP2 can cause DCM and knockout mice, either whole body (CAP2 KO) or cardiomyocyte specific knockouts (CAP2 CKO), develop DCM with cardiac conduction disease. RNA-seq analysis of CAP2 KO hearts and isolated cardiomyocytes revealed over-activation of fetal genes including serum response factor (SRF) regulated genes such as Myl9 and Acta2 prior to the emergence of cardiac disease. To test if we could treat CAP2 KO mice, we synthesized and tested the SRF inhibitor CCG-1423-8u. CCG-1423-8u reduced expression of the SRF targets Myl9 and Acta2, as well as the biomarker of heart failure, NPPA. The median survival of CAP2 CKO mice was 98 days, while CCG-1423-8u treated CKO mice survived for 116 days and also maintain normal cardiac function longer. These results suggest that some forms of sudden cardiac death and cardiac conduction disease are under cytoskeletal stress and that inhibiting signaling through SRF may benefit DCM by reducing cytoskeletal stress.

2019-02-22 | GSE125603 | GEO

Circulating cardiac microRNA-FOXO3 axis safeguards against dilated cardiomyopathy

Project description:Background - Cardiac microRNAs (miRNAs) could be released into circulation thus becoming circulating cardiac miRNAs, which are increasingly recognized as noninvasive and readily accessible biomarker for multiple heart diseases. A global loss of cardiac miRNAs due to dicer or dgcr8 depletion has been reported to lead to dilated cardiomyopathy (DCM). However, DCM-associated circulating miRNAs (DACMs) and their roles in regulating DCM progression remain largely unexplored. Methods and Results - Through miRNA sequencing of human plasma procured from DCM patients and healthy control people, DCM was characterized with a unique expression pattern for circulating miRNAs. Among them, miR-26a-5p, miR-30c-5p, miR-126-5p, and miR-126-3p were all identified with dramatic reductions in DCM mouse myocardium as in the plasma of DCM patients. FOXO3, highlighted as a predicted common target gene, was experimentally demonstrated to be repressed within cardiomyocytes by these miRNAs except miR-26a-5p. Mechanistically, miRNA combination (miR-30c-5p, miR-126-5p, and miR-126-3p) significantly attenuated FOXO3-induced apoptosis and autophagy observed in cardiomyocytes as well as in DCM murine heart. Cardiac-specific knockout of FOXO3 conspicuously mitigated myocardial apoptosis and autophagy in DCM development. Moreover, stymieing the interaction between these miRNAs and FOXO3 mRNA extremely crippled the cardioprotection of these miRNAs against DCM progression. Cardiac miRNA-FOXO3 axis plays a pivotal role in safeguarding against myocardial apoptosis and autophagy, thereby maintaining cardiac homeostasis and potently preventing DCM development. These findings may provide serological clues for the noninvasive diagnosis of DCM in the future, and unambiguously shed new light on DCM pathogenesis and associated therapeutic targets

2022-07-31 | GSE209991 | GEO

Abnormal circadian rhythms exacerbate dilated cardiomyopathy by reducing the ventricular mechanical strength

Project description:Dilated cardiomyopathy (DCM) has etiological and pathophysiological heterogeneity. Abnormal circadian rhythm (ACR) is related to the development of DCM in animal models, but exploration based on clinical samples is lacking. Sleep apnea (SA) is the most common disease related to ACR, and we chose SA as the study object to explore ACR-DCM. We included a DCM cohort and divided it into SA (n=76) and without SA group (n=29). RT-qPCR was used to determine the change of rhythm gene expression pattern. We used single-nucleus RNA sequencing (snRNA-seq) to explore the abnormal transcriptional patterns in the ACR group, and we verified the findings by pathological staining, atomic force microscopy (AFM), and Rev-erbα/β knockout (KO) mice analysis. DCM patients with SA showed decreased amplitude of rhythm gene expression. SA group showed more severe dilation of left heart chambers. From snRNA-seq, ACR-DCM lost the morning transcriptional patterns, detailly, actin cytoskeleton organization of cardiomyocytes (CMs) disrupted and hypertrophy aggravated, and the proportion of activated fibroblasts (Fibs) decreased with the reduction of fibrotic area ratio. The results of pathological staining, mechanical experiments, and transcriptional feature of Rev-erbα/β KO mice supported the above findings. The severe dilation of the left ventricular (LV) wall in DCM patients with SA was associated with a decrease in structural strength, and phenotypic changes of CMs and Fibs were involved in this process. ACR-DCM was histopathologically characterized by a fluffy ventricular wall.

2024-07-18 | GSE270258 | GEO

TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis

Project description:The mechanisms underlying cancer metastasis remain poorly understood. Here, we report that TFAM deficiency rapidly and stably induced spontaneous lung metastasis in mice with liver cancer. Interestingly, unexpected polymerization of nuclear actin was observed in TFAM-knockdown HCC cells when cytoskeleton was examined. Polymerization of nuclear actin is causally linked to the high-metastatic ability of HCC cells by modulating chromatin accessibility and coordinating the expression of genes associated with extracellular matrix remodeling, angiogenesis, and cell migration. Mechanistically, TFAM deficiency blocked the TCA cycle and increased the intracellular malonyl-CoA levels. Malonylation of mDia2, which drives actin assembly, promotes its nuclear translocation. Importantly, inhibition of malonyl-CoA production or nuclear actin polymerization significantly impeded the spread of HCC cells in mice. Moreover, TFAM was significantly downregulated in metastatic HCC tissues and was associated with overall survival and time to tumor recurrence of HCC patients. Taken together, our study connects mitochondria to the metastasis of human cancer via uncovered mitochondria-to-nucleus retrograde signaling, indicating that TFAM may serve as an effective target to block HCC metastasis.

2022-06-23 | MTBLS4307 | MetaboLights

Large-scale genetic screens identify BET-1 as a cytoskeleton regulator promoting actin health and lifespan

Project description:The actin cytoskeleton is a three-dimensional scaffold of proteins that is a regulatory, energy-consuming material with dynamic properties shaping the structure and function of the cell. The proper function of actin is required for many cellular pathways, including cell division, autophagy, chaperone function, endocytosis, and exocytosis (1–5). The breakdown of these cellular processes manifests during aging and exposure to stress, which is in part due to the breakdown of the actin cytoskeleton (5–9). However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well understood. Here, we performed a multi-pronged, cross-organismal screen combining a whole-genome CRISPR-Cas9 screen in human fibroblasts with in vivo C. elegans synthetic lethality screening. We identified the bromodomain protein, BET-1, as a key regulator promoting actin health and longevity. Interestingly, overexpression of bet-1 preserves actin health at late age and promotes lifespan and healthspan in C. elegans. These beneficial effects are through preservation of actin, downstream of the function of BET-1 as a transcriptional regulator. Together, our discovery attributes assigns a key role of BET-1 in cytoskeletal health, highlighting regulatory cellular networks promoting cytoskeletal homeostasis.

2023-06-01 | E-MTAB-12289 | biostudies-arrayexpress

Large-scale genetic screens identify BET-1 as a cytoskeleton regulator promoting actin health and lifespan

2023-06-01 | E-MTAB-11786 | biostudies-arrayexpress

A leiomodin 2 neonatal dilated cardiomyopathy causing mutation results inaltered actin-regulatory gene signatures andcardiomyocyte dysfunction

Project description:Neonatal dilated cardiomyopathy (DCM) is a poorly understood muscular disease of the heart. Several homozygous biallelic variants inLMOD2, the gene encoding the actin-binding protein Leiomodin 2, have been identified to result in severe DCM. Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting in neonatal death. Thus, it is evident that Lmod2 is essential to normal human cardiac muscle function. This study aimed to understand the underlying pathophysiology and signaling pathways related to the first reported LMOD2 variant (c.1193G>A, p.Trp398*). Using patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model harboring the homologous mutation to the patient, we discovered dysregulated actin-thin filament lengths, altered contractility and calcium handling properties, as well as alterations in the serum response factor (SRF)-dependent signaling pathway. These findings reveal that LMOD2 may be regulating SRF activity in an actin-dependent manner and provide a potential new strategy for the development of biologically active molecules to target LMOD2-related cardiomyopathies.

2024-10-10 | GSE271871 | GEO

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