GO:1905305 negative regulation of cardiac myofibril assembly: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1905305 describes any process that stops, prevents or reduces the frequency, rate or extent of cardiac myofibril assembly.
• Cardiac myofibril assembly is a tightly regulated process; its negative regulation is essential for proper heart development and function.
• Key proteins such as MEK5, CapZ, muscle LIM protein (MLP), and myosin-binding protein C (MyBP-C) are involved in modulating myofibril assembly.
• Dysregulation of negative regulation can lead to cardiac hypertrophy, heart failure, and other cardiomyopathies.
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) enable precise dissection of genes controlling this process.
• Understanding GO:1905305 provides insights into therapeutic targets for heart disease and regenerative medicine.
Description
The Gene Ontology (GO) term GO:1905305, negative regulation of cardiac myofibril assembly, refers to any process that stops, prevents or reduces the frequency, rate or extent of cardiac myofibril assembly. Cardiac myofibrils are the contractile units of cardiomyocytes, and their proper assembly is critical for heart function. This process is dynamically regulated during development and in response to stress, and its dysregulation contributes to various cardiac pathologies. Understanding the negative regulation of cardiac myofibril assembly is therefore essential for researchers studying heart development, hypertrophy, and heart failure. Recent studies have identified multiple signaling pathways and structural proteins that modulate myofibril assembly, including MEK5-ERK5 signaling, CapZ dynamics, and muscle LIM protein (MLP). These findings highlight the complexity of the regulatory networks and the need for precise experimental models to dissect gene function. This article provides a comprehensive overview of GO:1905305, covering its definition, biological significance, key genes, disease associations, and research methodologies, with a focus on CRISPR-based approaches for functional studies.
negative regulation of cardiac myofibril assembly At A Glance
| GO ID | GO:1905305 |
|---|---|
| GO term | negative regulation of cardiac myofibril assembly |
| Ontology | biological_process |
| Synonym | inhibition of cardiac myofibril assembly; downregulation of heart myofibril assembly; negative regulation of cardiac myofibril development |
| Major function | Inhibits the assembly of cardiac myofibrils, modulating heart muscle contraction and growth. |
| Related processes | cardiac myofibril assembly (GO:0010923), regulation of cardiac muscle hypertrophy |
| Key regulators | MEK5, CapZ, MLP, MyBP-C, RhoA/GATA4 |
| Disease relevance | Cardiac hypertrophy, heart failure, cardiomyopathies |
What Is GO:1905305?
GO:1905305 is a biological process term defined as any process that stops, prevents or reduces the frequency, rate or extent of cardiac myofibril assembly. It encompasses molecular mechanisms that inhibit the formation of myofibrils in cardiac muscle cells, including signaling pathways, protein modifications, and transcriptional regulation that ultimately downregulate the assembly process.
Why Is negative regulation of cardiac myofibril assembly Important in Cell Biology?
Negative regulation of cardiac myofibril assembly is crucial for maintaining proper heart structure and function. Excessive or uncontrolled myofibril assembly can lead to pathological cardiac hypertrophy, while insufficient assembly contributes to dilated cardiomyopathy and heart failure. Understanding the molecular players that inhibit this process provides potential therapeutic targets for modulating cardiac growth and regeneration.
• Prevents pathological cardiac hypertrophy by limiting excessive sarcomere assembly.
• Regulates heart development and maturation.
• Involved in the response to stress and injury in the myocardium.
• Dysregulation linked to heart failure and cardiomyopathies.
• Provides targets for therapeutic intervention in cardiac disease.
• Key for understanding signaling pathways like MEK5-ERK5 and RhoA.
• Influences actin cytoskeleton dynamics via CapZ.
• Modulated by post-translational modifications (phosphorylation, acetylation).
• Interacts with muscle LIM protein and myosin-binding protein C.
• Relevant for regenerative medicine and tissue engineering.
What Happens During negative regulation of cardiac myofibril assembly?
Signaling Pathways That Inhibit Myofibril Assembly
In simple terms: Certain signals tell the heart muscle cell to slow down or stop building new contractile units.
Negative regulation of cardiac myofibril assembly is often initiated by signaling pathways that respond to stress or developmental cues. For example, the MEK5-ERK5 pathway, when activated, can induce serial assembly of sarcomeres and eccentric cardiac hypertrophy, but its negative regulation may involve feedback mechanisms that limit excessive assembly. Additionally, RhoA signaling through GATA factors can modulate cardiac gene expression, influencing myofibril assembly. These pathways ultimately converge on downstream effectors that inhibit the assembly process.
Role of Actin Capping Protein CapZ
In simple terms: CapZ acts like a cap on the ends of actin filaments, controlling how they grow and assemble into myofibrils.
CapZ is an actin capping protein that regulates actin filament dynamics. Dual phosphorylation and acetylation of CapZ have been shown to regulate myofibril growth during cardiac hypertrophy. Negative regulation of myofibril assembly may involve modifications of CapZ that reduce its ability to promote actin polymerization, thereby inhibiting myofibril formation.
Muscle LIM Protein (MLP) and MyBP-C Complex
In simple terms: MLP and MyBP-C work together to control muscle differentiation; when their interaction is disrupted, myofibril assembly can be inhibited.
Muscle LIM protein (MLP) forms a complex with myosin-binding protein C (MyBP-C) that regulates muscle differentiation. Downregulation of MLP by nitric oxide impacts cardiac myocyte hypertrophy, suggesting that MLP levels are critical for myofibril assembly. Negative regulation may occur through disruption of this complex or reduced expression of its components.
Transcriptional Control by GATA Factors
In simple terms: GATA transcription factors can turn off genes needed for building myofibrils.
Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA and can repress or activate cardiac genes. Negative regulation of cardiac myofibril assembly may involve GATA-mediated repression of sarcomeric genes, thereby reducing the availability of building blocks for myofibril assembly.
Key Genes Involved in GO:1905305 negative regulation of cardiac myofibril assembly
The following genes and proteins have been implicated in the negative regulation of cardiac myofibril assembly, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| MEK5 | Activates ERK5; can induce serial sarcomere assembly but also subject to negative feedback | Studied in cardiac hypertrophy models |
| CapZ | Actin capping protein; regulates actin filament growth | Phosphorylation/acetylation controls myofibril growth |
| MLP (CSRP3) | Muscle LIM protein; forms complex with MyBP-C | Downregulation by NO impacts hypertrophy; complex regulates differentiation |
| MyBP-C (MYBPC3) | Myosin-binding protein C; structural and regulatory | Forms complex with MLP; mutations cause cardiomyopathy |
| RhoA | Small GTPase; regulates GATA factors | Tissue-specific GATA effectors in heart |
| GATA4 | Transcription factor; regulates cardiac genes | Effector of RhoA signaling |
| MYH7 | Beta-myosin heavy chain; sarcomeric protein | Zone-specific regulation of cardiac myosin |
| MYH6 | Alpha-myosin heavy chain; sarcomeric protein | Cardiac myosin regulation |
| FHOD3 | Formin; actin nucleation | Expressed in striated muscle; potential role in sarcomere assembly |
| MYO18A | Class 18 myosin; sarcomeric protein? | Specialist sarcomeric proteins? |
| MYO18B | Class 18 myosin; sarcomeric protein? | Specialist sarcomeric proteins? |
| ACTC1 | Cardiac actin; main component of thin filaments | Mutations cause cardiomyopathies |
| TNNT2 | Troponin T; regulates contraction | Mutations cause cardiomyopathies |
| MYL2 | Regulatory myosin light chain | Phosphorylation regulates assembly |
| NPPA | Atrial natriuretic peptide; marker of hypertrophy | Induced in hypertrophy |
| NPPB | Brain natriuretic peptide; marker of hypertrophy | Induced in hypertrophy |
How Is negative regulation of cardiac myofibril assembly Regulated?
The negative regulation of cardiac myofibril assembly is itself regulated by various upstream signals. The MEK5-ERK5 pathway can promote assembly, but negative feedback loops may inhibit it. Nitric oxide downregulates MLP, impacting hypertrophy. RhoA signaling through GATA factors can repress or activate genes. Additionally, post-translational modifications such as phosphorylation and acetylation of CapZ regulate myofibril growth. These regulatory mechanisms ensure precise control of myofibril assembly in response to physiological demands.
negative regulation of cardiac myofibril assembly and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| MEK5 | Cardiac hypertrophy | Overexpression and knockout mouse models |
| CSRP3 (MLP) | Hypertrophic cardiomyopathy, heart failure | Knockout mice, point mutations |
| MYBPC3 | Hypertrophic cardiomyopathy | Knock-in mice with human mutations |
| MYH7 | Hypertrophic/Dilated cardiomyopathy | CRISPR knock-in of mutations |
| GATA4 | Congenital heart defects | Cardiac-specific knockout |
Cardiac Hypertrophy and Heart Failure
Dysregulation of negative regulation of cardiac myofibril assembly can lead to pathological cardiac hypertrophy. For instance, activated MEK5 induces eccentric hypertrophy, but without proper negative regulation, this can progress to heart failure. Downregulation of MLP by nitric oxide also contributes to hypertrophic responses. Thus, loss of negative regulation may underlie hypertrophic cardiomyopathy.
Cardiomyopathies Linked to Sarcomeric Protein Mutations
Mutations in sarcomeric proteins such as MYH7, MYBPC3, and TNNT2 are associated with hypertrophic and dilated cardiomyopathies. These mutations may disrupt the balance between assembly and negative regulation, leading to impaired contractility.
Role in Heart Development
Proper negative regulation is essential during heart development to ensure correct chamber formation and myofibril organization. Disruption of GATA4 or RhoA signaling can lead to developmental defects.
From negative regulation of cardiac myofibril assembly-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X inhibit myofibril assembly? | Knockout of gene X in cardiomyocytes (CRISPR) |
| Does point mutation in gene Y affect assembly? | Point mutation knock-in via CRISPR |
| Does overexpression of gene Z reduce myofibril assembly? | Overexpression via lentivirus or CRISPR activation |
| Does tag affect protein localization? | Tagged knock-in (e.g., GFP) |
| Does gene W regulate hypertrophy in vivo? | Cardiac-specific knockout mouse |
| Does mutation in sarcomeric protein cause cardiomyopathy? | Patient-derived iPSCs with CRISPR correction |
How to Study the negative regulation of cardiac myofibril assembly Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screen | Loss-of-function phenotypes | Identify negative regulators |
| CRISPR activation screen | Gain-of-function phenotypes | Identify inhibitors of assembly |
| Immunofluorescence | Sarcomere structure and localization | Quantify myofibril assembly |
| Phosphoproteomics | Post-translational modifications | Study CapZ regulation |
| RNA-seq | Transcriptional changes | Identify GATA4 targets |
| Co-immunoprecipitation | Protein-protein interactions | Study MLP-MyBP-C complex |
| Contractility assay | Functional output | Assess hypertrophy |
| iPSC-derived cardiomyocytes | Human disease modeling | Test mutations |
CRISPR Screening for Regulators
Genome-wide CRISPR knockout or activation screens can identify genes that negatively regulate cardiac myofibril assembly. Using cardiomyocytes derived from iPSCs, researchers can screen for loss of sarcomere structure or function.
Imaging and Proteomics
High-content imaging of sarcomere proteins (e.g., actinin, myosin) allows quantification of myofibril assembly. Proteomics can reveal changes in protein interactions and post-translational modifications.
Transcriptomics and Epigenomics
RNA-seq and ChIP-seq can identify transcriptional changes and GATA4 binding sites during negative regulation.
Functional Assays
Contractility assays, calcium imaging, and electrophysiology measure the functional consequences of altered myofibril assembly.
How CRISPR Can Be Used to Study GO:1905305 negative regulation of cardiac myofibril assembly
Knockout
CRISPR knockout of candidate negative regulators (e.g., MEK5, CapZ) in cardiomyocytes can reveal their necessity for inhibiting myofibril assembly. For example, knockout of CapZ might lead to increased myofibril assembly.
Point Mutation
Introducing point mutations in sarcomeric genes (e.g., MYH7, MYBPC3) using CRISPR can model human cardiomyopathies and test their effects on myofibril assembly.
Knock-in
Knock-in of tagged proteins (e.g., GFP-MLP) allows live-cell imaging of protein dynamics during negative regulation.
Overexpression
CRISPR activation (CRISPRa) can overexpress genes to test if they inhibit myofibril assembly. For example, overexpression of MLP might suppress hypertrophy.
How EDITGENE Supports negative regulation of cardiac myofibril assembly Research
Researchers studying negative regulation of cardiac myofibril assembly-related genes often need to determine whether a candidate gene is causally involved in inhibiting myofibril formation. EDITGENE provides comprehensive CRISPR-based services to enable such functional studies.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of cardiac myofibril assembly research.
Frequently Asked Questions About negative regulation of cardiac myofibril assembly
What is GO:1905305?
GO:1905305 is a Gene Ontology term for negative regulation of cardiac myofibril assembly, describing processes that inhibit the formation of cardiac myofibrils.
What genes are involved in negative regulation of cardiac myofibril assembly?
Key genes include MEK5, CapZ, MLP (CSRP3), MyBP-C (MYBPC3), RhoA, and GATA4.
How is cardiac myofibril assembly negatively regulated?
Through signaling pathways (e.g., MEK5-ERK5), post-translational modifications of CapZ, and transcriptional repression by GATA factors.
What diseases are associated with dysregulation of this process?
Cardiac hypertrophy, heart failure, and cardiomyopathies.
What experimental models are used to study GO:1905305?
CRISPR knockout, point mutation, knock-in, overexpression in cardiomyocytes, and animal models.
How can CRISPR help study negative regulation of cardiac myofibril assembly?
CRISPR enables precise gene editing to create loss- or gain-of-function models, screening for regulators, and tagging proteins for imaging.
What is the role of CapZ in myofibril assembly?
CapZ caps actin filaments; its phosphorylation and acetylation regulate myofibril growth during hypertrophy.
How does MLP regulate myofibril assembly?
MLP forms a complex with MyBP-C to regulate muscle differentiation; its downregulation by nitric oxide impacts hypertrophy.
What signaling pathways inhibit myofibril assembly?
MEK5-ERK5, RhoA-GATA, and nitric oxide pathways are involved.
What methods are used to measure myofibril assembly?
Immunofluorescence, proteomics, RNA-seq, and contractility assays.
Conclusion
GO:1905305, negative regulation of cardiac myofibril assembly, is a critical biological process that maintains cardiac homeostasis. Its dysregulation contributes to major heart diseases, making it a prime target for therapeutic intervention. Advances in CRISPR technology and multi-omics approaches are accelerating our understanding of the underlying mechanisms. EDITGENE's comprehensive services empower researchers to dissect this process with precision and speed.
References
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- 2. Nicol RL et al.. 2001. Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy.. EMBO J 20(11):2757-67 PMID: 11387209
- 3. Horsthemke M et al.. 2024. Are the class 18 myosins Myo18A and Myo18B specialist sarcomeric proteins?. Front Physiol 15:1401717 PMID: 38784114
- 4. Lin YH et al.. 2016. Myofibril growth during cardiac hypertrophy is regulated through dual phosphorylation and acetylation of the actin capping protein CapZ.. Cell Signal 28(8):1015-24 PMID: 27185186
- 5. Nakagawa H et al.. 2024. The expression of the formin Fhod3 in mouse tongue striated muscle.. Cell Struct Funct 49(2):111-122 PMID: 39384365
- 6. Heineke J et al.. 2003. Downregulation of cytoskeletal muscle LIM protein by nitric oxide: impact on cardiac myocyte hypertrophy.. Circulation 107(10):1424-32 PMID: 12642365
- 7. Arvanitis DA et al.. 2017. Muscle Lim Protein and myosin binding protein C form a complex regulating muscle differentiation.. Biochim Biophys Acta Mol Cell Res 1864(12):2308-2321 PMID: 28867610
- 8. Charron F et al.. 2001. Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA.. Genes Dev 15(20):2702-19 PMID: 11641276
