Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cardiac Myofibrillogenesis 1 is Spatiotemporally Modulated by the Molecular Chaperone UNC45B

ABSTRACT: Sarcomeres are fundamental to cardiac muscle contraction. Their impairment can elicit cardiomyopathies, leading causes of death worldwide. However, the molecular mechanism underlying sarcomere assembly remains obscure. We used human embryonic stem cell (hESC)-derived cardiomyocytes (CMs) to reveal step-wise spatiotemporal regulation of core cardiac myofibrillogenesis-associated proteins. We found that the molecular chaperone UNC45B is highly co-expressed with KINDLIN2 (KIND2), a marker of protocostameres, and later its distribution overlaps with that of muscle myosin MYH6. UNC45B-knockout CMs display essentially no contractility. Our phenotypic analyses further reveal that: 1) binding of Z-line anchor protein ACTN2 to protocostameres is perturbed due to impaired protocostamere formation, resulting in ACTN2 accumulation; 2) F-ACTIN polymerization is suppressed; and 3) MYH6 becomes degraded, so it cannot replace non-muscle myosin MYH10. Our mechanistic study demonstrates that UNC45B mediates protocostamere formation by regulating KIND2 expression. Thus, we show that UNC45B modulates cardiac myofibrillogenesis by interacting spatiotemporally with various proteins.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229229 | GEO | 2023/08/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Alternative Splicing Mediated by RNA-binding Protein RBM24 Facilitates Cardiac Myofibrillogenesis in a Differentiation Stage-Specific Manner

Project description:We ablated RBM24 from human embryonic stem cells (hESCs) using CRISPR/Cas9 techniques. Although RBM24-/- hESCs still differentiated into sarcomere-hosting cardiomyocytes, they exhibited disrupted sarcomeric structures with punctate Z-lines due to impaired myosin replacement during early myofibrillogenesis. Transcriptomics revealed >4000 genes regulated by RBM24. Among them, core myofibrillogenesis proteins (e.g. ACTN2, TTN, and MYH10) were misspliced. Consequently, MYH6 cannot replace non-muscle myosin MYH10, leading to myofibrillogenesis arrest at the early premyofibril stage and causing disrupted sarcomeres. Intriguingly, we found that the actin-binding domain (ABD; encoded by exon 6) of the Z-line anchor protein ACTN2 is predominantly excluded from early cardiac differentiation, whereas it is consistently included in human adult heart. CRISPR/Cas9-mediated deletion of exon 6 from ACTN2 in hESCs, as well as forced expression of full-length ACTN2 in RBM24-/- hESCs, further corroborated that inclusion of exon 6 is critical for sarcomere assembly. Overall, we have demonstrated that RBM24-facilitated inclusion of exon 6 in ACTN2 at distinct stages of cardiac differentiation is evolutionarily conserved and crucial to sarcomere assembly and integrity.

2021-11-22 | GSE186518 | GEO

Cardiac Myofibrillogenesis is Spatiotemporally Modulated by the Molecular Chaperone UNC45B

Project description:Sarcomeres are fundamental to cardiac muscle contraction. Their impairment can elicit cardiomyopathies, leading causes of death worldwide. However, the molecular mechanism underlying sarcomere assembly remains obscure. We used human embryonic stem cell (hESC)-derived cardiomyocytes (CMs) to reveal step-wise spatiotemporal regulation of core cardiac myofibrillogenesis-associated proteins.

2023-10-24 | PXD042075 | Pride

The AP-1 Transcription Factor c-Jun Prevents Stress-Imposed Maladaptive Remodeling of the Heart

Project description:Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hyphertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload. Microarrays were used to identify specific genes that might be globally affected in the absence of c-jun in cardiomyocytes. Total RNA was extracted from the hearts of 10 weeks old Junf/f (n=2) and Jun delta mu (n=2) mice using TRIzol Reagent.

2013-09-19 | E-GEOD-47898 | biostudies-arrayexpress

Fast skeletal myosin binding protein-C regulates fast skeletal muscle contraction

Project description:Myosin-binding protein C (MyBP-C) is a thick filament regulatory protein found exclusively in the C-zone of the A band in the sarcomeres of vertebrate striated muscle. Cardiac, slow skeletal and fast skeletal MyBP-C (fMyBP-C) paralogs perform different functions. However, the functional role of fMyBP-C in fast skeletal muscle is completely unknown. Genetic mutations in human fMyBP-C lead to skeletal myopathies. All three isoforms share similar protein structures, but likely differ substantially in terms of expression and function, which may serve the distinct physiologies of fast and slow muscle fibers. In the present study, we developed a novel fMyBP-C global knockout (KO) mouse model (C2-/-) to investigate the structural, functional, molecular, cellular and physiological roles of fMyBP-C in skeletal muscle.

2021-04-09 | PXD022316 | Pride

Systematic transcriptomics reveals a biphasic mode of sarcomere morphogenesis in flight muscles regulated by Spalt

Project description:Muscles organise a pseudo-crystalline array of actin, myosin and titin filaments to build force-producing sarcomeres. To study how sarcomeres are built, we performed mRNA-sequencing of developing Drosophila flight muscles and identified 40 distinct expression profile clusters. Strikingly, two clusters are strongly enriched for sarcomeric components. Temporal gene expression together with detailed morphological analysis enabled us to define two distinct phases of sarcomere development, both of which require the transcriptional regulator Spalt major. During the first sarcomere formation phase, 2.0 µm long immature sarcomeres assemble myofibrils that spontaneously contract. In the second sarcomere maturation phase, sarcomeres grow to their final 3.2 µm length and 1.5 µm diameter and acquire stretch-sensitivity. Interestingly, the final number of myofibrils per flight muscle fiber is determined at the onset of the first phase and remains constant. Together, this defines a biphasic mode of sarcomere and myofibril morphogenesis – a new concept which may also apply to vertebrate muscle or heart development.

2017-12-01 | GSE107247 | GEO

The effect of HDAC inhibitor, 4b, on skeletal muscle gene expression

Project description:To assess the effects of histone deacetylase (HDAC) inhibitor, HDACi 4b, treatment on muscle function on a molecular level, we performed microarray analysis on skeletal muscle (gastrocnemius) samples from wt and N17182Q mice treated with the HDAC inhibitor 4b for 3 months (50 mg/kg; s.c. injection 3x weekly; n=4 per group). The transcriptome pattern in N17182Q mice compared to wt controls consisted of deficits in the expression of genes related to mitochondrial function and oxidative metabolism. In addition, we noted that numerous genes associated with basal contractile function were altered in HD N17182Q mice. These include genes related to the muscle contractile complex, Tnnt3 and Myh8, as well as several additional myosin genes: myosin heavy chain genes, Myh10 and Myh4, and myosin light chain genes, Myl1, Mylc2 and Mylk. These findings implicate deficits in the underlying contractile function in skeletal muscle from HD mice. Further, we found robust effects of 4b treatment on the expression of genes in skeletal muscle, with 556 genes showing significantly altered expression, at p<0.005, in 4b-treated N17182Q muscle compared to vehicle-treated control mice. n=4 vehicle-treated WT mice, n=5 HDACi 4b-treated WT mice, n=4 vehicle-treated N17182Q transgenic mice, and n=3 HDACi 4b-treated N17182Q transgenic mice.

2014-11-01 | E-GEOD-56963 | biostudies-arrayexpress

The AP-1 Transcription Factor c-Jun Prevents Stress-Imposed Maladaptive Remodeling of the Heart

2013-09-19 | GSE47898 | GEO

The effect of HDAC inhibitor, 4b, on skeletal muscle gene expression

2014-11-01 | GSE56963 | GEO

Myh10 deficiency leads to defective extracellular matrix remodeling and pulmonary disease

Project description:Impaired alveolar formation and maintenance are features of many pulmonary diseases that are associated with significant morbidity and mortality. In a forward genetic screen for modulators of mouse lung development, we identified the non-muscle myosin II heavy chain gene, Myh10. Myh10 mutant pups exhibit cyanosis and respiratory distress, and die shortly after birth from differentiation defects in alveolar epithelium and mesenchyme. From omics analyses and follow up studies, we find decreased Thrombospondin expression accompanied with increased matrix metalloproteinase activity in both mutant lungs and cultured mutant fibroblasts, as well as disrupted extracellular matrix (ECM) remodeling. Loss of Myh10 specifically in mesenchymal cells results in ECM deposition defects and alveolar simplification. Notably, MYH10 expression is down-regulated in the lung of emphysema patients. Altogether, our findings reveal critical roles for Myh10 in alveologenesis at least in part via the regulation of ECM remodeling, which may contribute to the pathogenesis of emphysema.

2018-09-19 | PXD011139 | Pride

Expression dynamics of HAND1/2 in in vitro human cardiomyocyte differentiation

Project description:Hand1 and Hand2 are transcriptional factors, and knockout mice of these genes show left and right ventricular hypoplasia, respectively. However, their function and expression in human cardiogenesis are not well studied. To delineate their expressions and assess their functions in human cardiomyocytes (CMs) in vitro, we established two triple reporter human induced pluripotent stem cell lines, HAND1mCherry, HAND2EGFP, with MYH6-driven iRFP670 or constitutive tagBFP expression and investigated their expression dynamics during cardiac differentiation. On day 5 of the differentiation, HAND1 expression marked cardiac progenitor cells. We profiled the CM subpopulations on day 20 with RNA-sequencing and found that mCherry+ CMs showed higher proliferative ability than mCherry- CMs and identified CD105 as a surface marker of highly proliferative CMs. Finally, we revealed that LEF1 is a key regulator of proliferation and is repressively regulated by HAND1 and HAND2.

2021-07-22 | GSE156394 | 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