GO:1904027 negative regulation of collagen fibril organization: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1904027 describes any process that stops, prevents, or reduces the frequency, rate, or extent of collagen fibril organization.
• Collagen fibril organization is essential for the structural integrity of the extracellular matrix (ECM) in tissues such as bone, tendon, cornea, and skin [3,5].
• Negative regulation of this process is critical for preventing pathological fibrosis, maintaining tissue homeostasis, and regulating cell motility [1,5].
• Key molecular players include CCN1, Coronin 1C, Csk, and collagen V, which modulate fibril assembly and alignment through diverse mechanisms [1,2,5,6].
• Dysregulation of collagen fibril organization is implicated in myocardial infarction, corneal anomalies, tendon healing defects, and cancer progression [1,2,5,6].
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) enable precise dissection of the regulatory mechanisms governing collagen fibril organization [2,5].
Description
Collagen fibril organization is a fundamental biological process that governs the assembly, alignment, and cross-linking of collagen molecules into fibrils, which provide tensile strength and structural support to the extracellular matrix (ECM). The Gene Ontology (GO) term GO:1904027, negative regulation of collagen fibril organization, encompasses any process that stops, prevents, or reduces the frequency, rate, or extent of this assembly. This regulatory process is essential for normal tissue development and homeostasis, and its dysregulation is associated with a spectrum of human pathologies, including fibrosis, impaired wound healing, and cancer [1,5]. Research into GO:1904027 has revealed that collagen fibril organization is not a passive self-assembly process but is actively modulated by a variety of matricellular proteins, intracellular signaling molecules, and microRNAs [1,2,7]. For instance, the matricellular protein CCN1 promotes collagen alignment and scar integrity after myocardial infarction, while Coronin 1C regulates MT1-MMP traffic and invadopodia function to influence collagen degradation and tumor invasiveness [1,2]. These findings underscore the importance of understanding the negative regulatory mechanisms that fine-tune collagen fibril organization in health and disease. This article provides a comprehensive overview of GO:1904027, integrating authoritative QuickGO data with real PubMed literature. We explore the molecular mechanisms, key genes, disease associations, and cutting-edge research methods, including CRISPR-based models, that are advancing our understanding of this critical regulatory process [3,5,6].
negative regulation of collagen fibril organization At A Glance
| GO ID | GO:1904027 |
|---|---|
| GO term | negative regulation of collagen fibril organization |
| Ontology | biological_process |
| Synonym | down regulation of collagen fibril organisation, down-regulation of collagen fibril organisation, downregulation of collagen fibril organisation, down regulation of collagen fibril organization, down-regulation of collagen fibril organization, downregulation of collagen fibril organization, down regulation of fibrillar collagen organization, down-regulation of fibrillar collagen organization, downregulation of fibrillar collagen organization, inhibition of collagen fibril organisation, inhibition of collagen fibril organization, inhibition of fibrillar collagen organization, negative regulation of collagen fibril organisation, negative regulation of fibrillar collagen organization |
| Major function | To stop, prevent, or reduce the frequency, rate, or extent of collagen fibril organization, thereby modulating extracellular matrix assembly and tissue architecture. |
| Biological context | Extracellular matrix remodeling, tissue development, wound healing, and disease pathogenesis [1,5]. |
| Key regulators | CCN1, Coronin 1C, Csk, collagen V, microRNAs [1,2,5,6,7]. |
| Associated diseases | Myocardial infarction, corneal anomalies, tendon healing defects, cancer [1,2,5,6]. |
| Research methods | CRISPR knockout, point mutation, knock-in, overexpression, RNA-seq, proteomics, imaging [2,5]. |
What Is GO:1904027?
GO:1904027, negative regulation of collagen fibril organization, is defined as any process that stops, prevents, or reduces the frequency, rate, or extent of collagen fibril organization. This biological process acts as a brake on the assembly of collagen molecules into ordered fibrillar structures, which are essential components of the extracellular matrix. It encompasses molecular events such as the inhibition of collagen fibril nucleation, the disruption of fibril elongation, or the promotion of fibril disassembly, ultimately influencing tissue architecture and function [3,5].
Why Is negative regulation of collagen fibril organization Important in Cell Biology?
Understanding negative regulation of collagen fibril organization (GO:1904027) is crucial because collagen fibrils are the primary structural components of the extracellular matrix, and their organization directly impacts tissue mechanics, cell signaling, and organ function. Dysregulation of this process can lead to pathological conditions such as fibrosis, where excessive collagen deposition impairs tissue function, or weakened ECM that compromises tissue integrity [1,5]. Moreover, collagen fibril organization influences cell migration, proliferation, and differentiation, making it a key player in cancer progression and metastasis. By elucidating the molecular mechanisms that negatively regulate collagen fibril organization, researchers can identify novel therapeutic targets for a range of diseases, from cardiovascular disorders to connective tissue diseases and cancer [1,2,5,6].
• Maintains tissue homeostasis by preventing excessive collagen deposition and fibrosis.
• Regulates ECM stiffness and mechanotransduction, influencing cell behavior and differentiation.
• Critical for proper wound healing and scar formation after tissue injury [1,6].
• Modulates cell motility and invasion, with implications for cancer metastasis.
• Plays a role in corneal transparency and vision, as dysregulation leads to corneal anomalies.
• Influences tendon healing outcomes, with collagen V deficiency affecting healing severity.
• Involved in bone mineralization and skeletal integrity through collagen fibril organization.
• Linked to atrial fibrillation through microRNA-mediated regulation.
• Provides targets for therapeutic intervention in fibrotic diseases and cancer [1,2].
• Serves as a model process for studying ECM assembly and regulation [3,5].
What Happens During negative regulation of collagen fibril organization?
Initiation of negative regulation
In simple terms: The process begins when specific molecules signal to stop collagen fibrils from forming or assembling further.
Negative regulation of collagen fibril organization is initiated by extracellular or intracellular signals that counteract the assembly process. For example, matricellular proteins such as CCN1 can modulate collagen alignment and scar integrity after myocardial infarction, indicating a role in regulating fibril organization. Similarly, microRNAs can post-transcriptionally repress genes involved in collagen fibril assembly, as seen in atrial fibrillation. These initiating signals set off a cascade of molecular events that ultimately reduce the frequency, rate, or extent of collagen fibril organization.
Inhibition of fibril elongation and cross-linking
In simple terms: Once the stop signal is received, the elongation of collagen fibrils and their cross-linking are slowed or blocked.
Following initiation, negative regulation can directly inhibit the elongation of collagen fibrils and their cross-linking. This may involve the action of proteases that cleave collagen molecules, or the binding of inhibitory proteins that block the sites required for fibril assembly. For instance, Coronin 1C regulates MT1-MMP traffic and invadopodia function, which can lead to collagen degradation and reduced fibril organization in triple-negative breast cancer. Additionally, collagen V deficiency during tendon healing results in distinct healing outcomes based on knockdown severity, suggesting that collagen V is required for proper fibril organization and its absence can lead to negative regulation.
Disruption of fibril alignment and architecture
In simple terms: The organized, parallel arrangement of collagen fibrils is disrupted, leading to a disorganized matrix.
Negative regulation of collagen fibril organization can also manifest as disruption of fibril alignment and architecture. In a study on corneal anomaly, ablation of Csk in neural crest lineages caused deregulation of collagen fibril organization and cell motility, resulting in abnormal corneal structure. This suggests that Csk normally acts to maintain organized collagen fibrils, and its loss leads to negative regulation. Similarly, mineral tessellation in bone and the stenciling principle for extracellular matrix mineralization highlight the importance of precise fibril organization for proper mineralization, and negative regulation could disrupt this process.
Cellular responses and motility
In simple terms: Changes in collagen fibril organization affect how cells move and interact with their environment.
The negative regulation of collagen fibril organization is closely linked to cellular responses such as motility and invasion. Coronin 1C promotes triple-negative breast cancer invasiveness through regulation of MT1-MMP traffic and invadopodia function, which involves collagen degradation and reorganization. This indicates that negative regulation of collagen fibril organization can facilitate cell migration and invasion, contributing to cancer progression. Furthermore, Csk ablation in neural crest lineages caused deregulation of collagen fibril organization and cell motility, linking fibril organization to cell movement.
Feedback and crosstalk with other ECM components
In simple terms: The process is fine-tuned by feedback loops and interactions with other matrix molecules.
Negative regulation of collagen fibril organization is not an isolated process; it is influenced by feedback mechanisms and crosstalk with other extracellular matrix components. For example, the collagenome in breast cancer involves mechanotransduction and microenvironmental cues that can modulate collagen fibril organization. Additionally, microRNAs such as those involved in atrial fibrillation can regulate multiple targets in the collagen synthesis and assembly pathways, providing a layer of post-transcriptional control. These feedback loops ensure that collagen fibril organization is dynamically regulated in response to physiological and pathological stimuli [3,8].
Key Genes Involved in GO:1904027 negative regulation of collagen fibril organization
The following genes and proteins have been experimentally implicated in the negative regulation of collagen fibril organization, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CCN1 | Matricellular protein that promotes collagen alignment and scar integrity after myocardial infarction | Studied in cardiac repair and fibrosis models |
| CORO1C | Regulates MT1-MMP traffic and invadopodia function, influencing collagen degradation and cancer invasiveness | Target in triple-negative breast cancer research |
| CSK | Ablation in neural crest lineages causes corneal anomaly by deregulating collagen fibril organization and cell motility | Used to study corneal development and ECM regulation |
| COL5A1 | Collagen V deficiency during tendon healing results in distinct healing outcomes based on knockdown severity | Model for tendon healing and collagen fibril assembly |
| COL5A2 | Component of collagen V, involved in fibril organization and tendon healing | Studied in connective tissue disorders |
| MMP14 | MT1-MMP, regulated by Coronin 1C, degrades collagen and affects fibril organization | Target in cancer invasion and metastasis |
| MIR21 | MicroRNA implicated in atrial fibrillation, potentially regulating collagen fibril organization | Biomarker and therapeutic target in cardiovascular disease |
| MIR29 | MicroRNA family known to regulate collagen expression and fibrosis | Studied in fibrosis and atrial fibrillation |
| MIR133 | MicroRNA involved in cardiac remodeling and collagen regulation | Research in atrial fibrillation and heart failure |
| COL1A1 | Major fibrillar collagen; its organization is subject to negative regulation | Fundamental to bone and tissue ECM studies |
| COL1A2 | Component of type I collagen fibrils; regulated in organization | Model for bone mineralization and ECM assembly |
| COL3A1 | Fibrillar collagen involved in tissue repair and fibrosis | Studied in wound healing and scar formation |
| FN1 | Fibronectin, an ECM protein that interacts with collagen and influences fibril organization | Used in ECM assembly and cell adhesion studies |
| LOX | Lysyl oxidase, cross-links collagen and affects fibril organization | Target in fibrosis and cancer |
| TGFB1 | Cytokine that regulates collagen synthesis and fibril organization | Central to fibrosis research |
| CTGF | Connective tissue growth factor, modulates collagen deposition and organization | Studied in fibrotic diseases |
| SPARC | Matricellular protein that regulates collagen fibril assembly | Research in bone and tissue remodeling |
| DCN | Decorin, a proteoglycan that regulates collagen fibrillogenesis | Model for corneal and tendon research |
How Is negative regulation of collagen fibril organization Regulated?
The negative regulation of collagen fibril organization is controlled by a complex network of signaling pathways and molecular regulators. MicroRNAs, such as those implicated in atrial fibrillation, can post-transcriptionally repress genes involved in collagen synthesis and assembly, thereby reducing fibril organization. Matricellular proteins like CCN1 can modulate collagen alignment and scar integrity after myocardial infarction, acting as positive or negative regulators depending on context. Intracellular kinases such as Csk play a role in maintaining organized collagen fibrils, and their ablation leads to deregulation. Additionally, collagen V levels influence tendon healing outcomes, suggesting a dose-dependent regulatory mechanism. These diverse regulatory inputs ensure that collagen fibril organization is dynamically adjusted to meet physiological demands and respond to injury or disease [1,5,6,7].
negative regulation of collagen fibril organization and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CCN1 | Myocardial infarction, cardiac fibrosis | Knockout mouse model of myocardial infarction |
| CORO1C | Triple-negative breast cancer invasiveness | Knockdown in breast cancer cell lines |
| CSK | Corneal anomaly, cell motility defects | Neural crest-specific knockout mouse |
| COL5A1 | Tendon healing defects, Ehlers-Danlos syndrome | Inducible knockdown in murine tendon healing model |
| MIR21 | Atrial fibrillation, cardiac fibrosis | Overexpression or knockout in cardiac cells |
Cardiovascular disease and myocardial infarction
Negative regulation of collagen fibril organization is critically involved in cardiac repair after myocardial infarction. The matricellular protein CCN1 promotes collagen alignment and scar integrity, and its dysregulation can lead to impaired scar formation and adverse cardiac remodeling. MicroRNAs have also been implicated in atrial fibrillation, where altered collagen fibril organization contributes to structural remodeling of the atria. These findings highlight the importance of tight regulation of collagen fibril organization in maintaining cardiac function and preventing pathological fibrosis [1,7].
Cancer progression and metastasis
In cancer, negative regulation of collagen fibril organization can promote tumor invasiveness and metastasis. Coronin 1C regulates MT1-MMP traffic and invadopodia function, leading to collagen degradation and enhanced invasiveness in triple-negative breast cancer. The collagenome in breast cancer is remodeled through mechanotransduction and microenvironmental interactions, and dysregulated collagen fibril organization can facilitate cancer cell migration. Thus, targeting the negative regulation of collagen fibril organization may offer therapeutic opportunities to limit cancer spread [2,8].
Corneal anomalies and connective tissue disorders
Ablation of Csk in neural crest lineages causes corneal anomaly by deregulating collagen fibril organization and cell motility, demonstrating the importance of negative regulation in corneal transparency and structure. Collagen V deficiency during tendon healing results in distinct healing outcomes based on knockdown severity, indicating that proper regulation of collagen fibril organization is essential for tendon repair. These examples underscore the role of negative regulation in maintaining connective tissue integrity and function [5,6].
Bone mineralization and skeletal health
Mineral tessellation in bone and the stenciling principle for extracellular matrix mineralization rely on precise collagen fibril organization. Negative regulation of this process could disrupt the ordered deposition of minerals, leading to skeletal abnormalities. Although direct evidence is limited, the interplay between collagen fibrils and mineralization suggests that regulators of fibril organization may influence bone quality and strength.
From negative regulation of collagen fibril organization-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of CCN1 impair collagen alignment after myocardial infarction? | CCN1 knockout mouse |
| How does Coronin 1C regulate MT1-MMP traffic and invadopodia? | CORO1C knockout in breast cancer cells |
| What is the effect of Csk ablation on corneal collagen fibril organization? | Neural crest-specific Csk knockout mouse |
| How does collagen V dosage affect tendon healing? | Col5a1 knockdown mouse models |
| Can microRNA inhibition restore normal collagen fibril organization in atrial fibrillation? | miR-21 knockout or antagomir treatment in cardiac cells |
| What is the role of collagen fibril organization in bone mineralization? | Col1a1 point mutation knock-in mouse |
How to Study the negative regulation of collagen fibril organization Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcript levels of collagen genes and regulators | Identifying differentially expressed genes in fibrosis or cancer [4,8] |
| Proteomics | Protein abundance and modifications of ECM components | Quantifying collagen cross-links and fibril composition |
| SHG microscopy | Collagen fibril alignment and density | Assessing scar integrity after myocardial infarction |
| TEM | Fibril diameter and ultrastructure | Studying corneal collagen organization |
| CRISPR knockout | Loss-of-function effects on fibril organization | Validating candidate negative regulators [2,5] |
| CRISPR activation (CRISPRa) | Gain-of-function effects on fibril organization | Overexpressing regulators to test sufficiency |
| Invadopodia assays | Matrix degradation activity | Measuring cancer cell invasiveness |
| Biochemical cross-link analysis | Collagen cross-link content | Evaluating fibril maturation and stability |
Genomic and transcriptomic profiling
RNA sequencing (RNA-seq) and single-cell RNA-seq can identify genes and microRNAs differentially expressed during negative regulation of collagen fibril organization. For example, network visualization of genes involved in skeletal muscle myogenesis in livestock animals has revealed co-expression modules related to ECM organization. In cancer, transcriptomic profiling of the collagenome in breast cancer has uncovered mechanotransduction pathways that regulate collagen fibril organization. These methods provide a global view of the regulatory landscape [4,8].
Proteomic and biochemical assays
Mass spectrometry-based proteomics can quantify collagen and its post-translational modifications, revealing changes in fibril organization. Biochemical assays such as hydroxyproline content and collagen cross-link analysis provide complementary information. For instance, mineral tessellation in bone has been studied using biochemical and imaging techniques to understand the stenciling principle. These approaches are essential for validating findings from genomic studies.
Imaging and structural analysis
Advanced imaging techniques, including second harmonic generation (SHG) microscopy, transmission electron microscopy (TEM), and atomic force microscopy (AFM), allow direct visualization of collagen fibril organization at high resolution. These methods have been used to assess collagen alignment after myocardial infarction and in corneal anomalies [1,5]. They provide spatial and structural information critical for understanding negative regulation [1,5].
Functional assays and CRISPR screens
CRISPR-based functional screens can identify genes that negatively regulate collagen fibril organization. For example, knockout of CORO1C in breast cancer cells has been used to study invadopodia function and collagen degradation. Similarly, Csk ablation in neural crest lineages has been achieved using conditional knockout mice. These functional assays are powerful for dissecting causal relationships [2,5].
How CRISPR Can Be Used to Study GO:1904027 negative regulation of collagen fibril organization
Knockout
CRISPR knockout (KO) is used to completely ablate genes suspected to negatively regulate collagen fibril organization. For example, knockout of CORO1C in triple-negative breast cancer cells has been used to study its role in MT1-MMP traffic and invadopodia function, revealing its impact on collagen degradation and invasiveness. Similarly, conditional knockout of Csk in neural crest lineages has demonstrated its essential role in maintaining corneal collagen fibril organization. KO models provide definitive loss-of-function evidence for gene function [2,5].
Point Mutation
CRISPR point mutation (base editing or prime editing) allows the introduction of specific amino acid substitutions to dissect domain functions or post-translational modification sites in regulators of collagen fibril organization. For instance, mutating phosphorylation sites in Csk could reveal how its kinase activity is regulated during corneal development. Point mutations in collagen genes can also model human connective tissue disorders and their effects on fibril organization.
Knock-in
CRISPR knock-in (KI) enables the insertion of reporter tags, such as fluorescent proteins or epitope tags, into endogenous loci to track protein localization and dynamics. For example, knocking in a GFP tag into COL5A1 would allow real-time imaging of collagen V during tendon healing. KI of disease-associated mutations can also create accurate models for studying negative regulation of collagen fibril organization in a physiological context.
Overexpression
CRISPR activation (CRISPRa) or traditional overexpression constructs can drive high-level expression of candidate negative regulators to test sufficiency. Overexpressing CCN1 in cardiac fibroblasts, for example, could enhance collagen alignment and scar integrity after myocardial infarction. Overexpression of microRNAs such as miR-21 in cardiac cells can mimic atrial fibrillation-associated changes in collagen fibril organization. These gain-of-function models complement KO studies [1,7].
How EDITGENE Supports negative regulation of collagen fibril organization Research
Researchers studying negative regulation of collagen fibril organization-related genes often need to determine whether a candidate gene is causally involved in modulating fibril assembly, alignment, or degradation. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this research, from gene knockout to precise point mutations, knock-in reporters, and overexpression models, as well as high-throughput library screening and bioinformatics analysis.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of collagen fibril organization research.
Frequently Asked Questions About negative regulation of collagen fibril organization
What is GO:1904027?
GO:1904027 is the Gene Ontology term for negative regulation of collagen fibril organization, defined as any process that stops, prevents, or reduces the frequency, rate, or extent of collagen fibril organization.
What genes are involved in negative regulation of collagen fibril organization?
Key genes include CCN1, CORO1C, CSK, COL5A1, COL5A2, MMP14, and various microRNAs such as MIR21, MIR29, and MIR133 [1,2,5,6,7].
How is collagen fibril organization negatively regulated?
It is regulated by matricellular proteins, intracellular kinases, microRNAs, and proteases that inhibit fibril elongation, disrupt alignment, or promote degradation [1,2,5,7].
What diseases are associated with dysregulation of collagen fibril organization?
Diseases include myocardial infarction, corneal anomalies, tendon healing defects, cancer progression, and atrial fibrillation [1,2,5,6,7].
What research methods are used to study negative regulation of collagen fibril organization?
Methods include RNA-seq, proteomics, SHG microscopy, TEM, CRISPR knockout, point mutation, knock-in, overexpression, and CRISPR library screening [2,3,4,5,8].
How does CCN1 regulate collagen fibril organization?
CCN1 promotes collagen alignment and scar integrity after myocardial infarction, acting as a matricellular protein that modulates fibril organization.
What is the role of Coronin 1C in collagen fibril organization?
Coronin 1C regulates MT1-MMP traffic and invadopodia function, leading to collagen degradation and enhanced cancer cell invasiveness.
How does Csk affect collagen fibril organization?
Ablation of Csk in neural crest lineages causes corneal anomaly by deregulating collagen fibril organization and cell motility.
What is the impact of collagen V deficiency on tendon healing?
Collagen V deficiency during murine tendon healing results in distinct healing outcomes based on knockdown severity, indicating its importance in fibril organization.
Can CRISPR be used to study negative regulation of collagen fibril organization?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models enable precise dissection of gene function in this process [2,5].
Conclusion
The negative regulation of collagen fibril organization (GO:1904027) is a critical biological process that maintains extracellular matrix homeostasis and influences tissue development, repair, and disease. Key regulators such as CCN1, Coronin 1C, Csk, and collagen V have been shown to modulate fibril assembly and alignment, with dysregulation linked to cardiovascular disease, cancer, and connective tissue disorders [1,2,5,6]. Advances in CRISPR-based models and high-throughput screening are accelerating the discovery of novel regulatory mechanisms and therapeutic targets [2,5]. EDITGENE provides comprehensive CRISPR services to support research on GO:1904027, from knockout and point mutation to knock-in, overexpression, and library screening, empowering scientists to unravel the complexities of collagen fibril organization and translate findings into clinical applications.
References
- 1. Fischer AG et al.. 2024. Matricellular protein CCN1 promotes collagen alignment and scar integrity after myocardial infarction.. Matrix Biol 133:14-32 PMID: 39098433
- 2. Castagnino A et al.. 2018. Coronin 1C promotes triple-negative breast cancer invasiveness through regulation of MT1-MMP traffic and invadopodia function.. Oncogene 37(50):6425-6441 PMID: 30065298
- 3. McKee MD et al.. 2022. Mineral tessellation in bone and the stenciling principle for extracellular matrix mineralization.. J Struct Biol 214(1):107823 PMID: 34915130
- 4. Nejad FM et al.. 2024. Network visualization of genes involved in skeletal muscle myogenesis in livestock animals.. BMC Genomics 25(1):294 PMID: 38504177
- 5. Takatsuka A et al.. 2008. Ablation of Csk in neural crest lineages causes corneal anomaly by deregulating collagen fibril organization and cell motility.. Dev Biol 315(2):474-88 PMID: 18262517
- 6. Leiphart RJ et al.. 2022. Collagen V deficiency during murine tendon healing results in distinct healing outcomes based on knockdown severity.. J Biomech 144:111315 PMID: 36201909
- 7. Shi KH et al.. 2013. Role of microRNAs in atrial fibrillation: new insights and perspectives.. Cell Signal 25(11):2079-84 PMID: 23811146
- 8. Vigo-Díaz N et al.. 2026. Decoding the Collagenome in Breast Cancer: Mechanotransduction, Microenvironment, and Translational Opportunities.. Int J Mol Sci 27(15) PMID: 42589449
