GO:0060231 mesenchymal to epithelial transition: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0060231 (mesenchymal to epithelial transition, MET) is the biological process in which a mesenchymal cell acquires apical/basolateral polarity, forms intercellular adhesive junctions, synthesizes basement membrane components, and becomes an epithelial cell.
• MET is the reverse of epithelial-to-mesenchymal transition (EMT); both are reversible and are driven by changes in gene expression, cell adhesion, and cytoskeletal organization.
• MET is essential during embryonic development, including the formation of the lateral plate mesoderm and the epithelialization of somites and kidney tubules.
• In cancer, MET can promote colonization at metastatic sites, allowing disseminated mesenchymal tumor cells to form epithelial-like secondary tumors.
• Key molecular players include E-cadherin (CDH1), tight junction proteins (e.g., TJP1/ZO-1), and basement membrane components such as laminins and collagen IV.
• Research on MET uses CRISPR knockout, knock-in, overexpression models, RNA-seq, proteomics, and imaging to dissect the regulatory networks and cellular changes.
Description
Mesenchymal to epithelial transition (MET) is a fundamental cellular process defined by GO:0060231, in which a mesenchymal cell changes into an epithelial cell by establishing apical/basolateral polarity, forming intercellular adhesive junctions, synthesizing basement membrane components, and adopting an epithelial morphology. This process is the reverse of epithelial-to-mesenchymal transition (EMT), and together they regulate cell plasticity during development and disease. MET is critical for normal embryogenesis, tissue repair, and organ formation, and its dysregulation contributes to cancer progression and metastasis. Understanding MET is therefore essential for researchers studying developmental biology, cancer biology, and regenerative medicine.
mesenchymal to epithelial transition At A Glance
| GO ID | GO:0060231 |
|---|---|
| GO term | mesenchymal to epithelial transition |
| Ontology | biological_process |
| Synonym | epithelial cell differentiation from mesenchymal cell; mesenchymal-epithelial transition |
| Major function | Conversion of a mesenchymal cell into an epithelial cell with apical/basolateral polarity, adhesive junctions, and basement membrane synthesis |
| Related process | Epithelial-to-mesenchymal transition (EMT), the reverse process |
| Key cellular changes | Cytoskeletal reorganization, E-cadherin upregulation, tight junction formation, basement membrane deposition |
| Developmental role | Essential for somitogenesis, kidney development, and lateral plate mesoderm epithelialization |
What Is GO:0060231?
According to the Gene Ontology, GO:0060231 (mesenchymal to epithelial transition) is a biological process in which a mesenchymal cell establishes apical/basolateral polarity, forms intercellular adhesive junctions, synthesizes basement membrane components, and becomes an epithelial cell. This definition captures the morphological and molecular hallmarks of MET, including the reorganization of the cytoskeleton, the switch from mesenchymal to epithelial gene expression programs, and the acquisition of cell-cell adhesion structures.
Why Is mesenchymal to epithelial transition Important in Cell Biology?
MET is important because it governs fundamental aspects of cell identity and tissue architecture, and its dysregulation is linked to cancer metastasis, fibrosis, and developmental disorders. In cancer, MET enables disseminated mesenchymal tumor cells to colonize distant organs and form epithelial-like metastases, making it a potential therapeutic target. In development, MET is required for the formation of epithelial tissues from mesenchymal precursors, such as during kidney tubulogenesis and somite epithelialization. Understanding MET mechanisms can inform strategies for regenerative medicine and cancer treatment.
• MET is essential for embryonic development, including the formation of the lateral plate mesoderm and epithelial organs.
• MET is the reverse of EMT, and the balance between these processes regulates cell plasticity in development and disease.
• In cancer, MET promotes metastatic colonization by allowing mesenchymal tumor cells to form epithelial-like secondary tumors.
• MET is involved in tissue repair and fibrosis, where epithelial regeneration requires MET-like transitions.
• Key molecular markers of MET include E-cadherin, ZO-1, and laminin, which are used to monitor the transition.
• MET is regulated by signaling pathways such as TGF-beta, which can induce EMT and inhibit MET.
• Studying MET helps identify therapeutic targets for cancer metastasis and fibrotic diseases.
• CRISPR-based models (knockout, knock-in, overexpression) enable functional dissection of MET regulators.
• MET research benefits from multi-omics approaches, including RNA-seq and proteomics, to map gene expression changes.
• Understanding MET can aid in generating epithelial cells from mesenchymal stem cells for regenerative medicine.
What Happens During mesenchymal to epithelial transition?
Initiation and Loss of Mesenchymal Traits
In simple terms: The cell starts to stop behaving like a mesenchymal cell.
During MET, mesenchymal cells downregulate mesenchymal markers such as vimentin and N-cadherin, and reduce migratory and invasive properties. This initiation phase is often triggered by changes in the extracellular environment or signaling cues that suppress EMT-inducing pathways like TGF-beta. The cell begins to reorganize its cytoskeleton and reduce stress fiber formation, preparing for epithelial polarization.
Establishment of Apical/Basolateral Polarity
In simple terms: The cell develops a top and bottom side, like a brick in a wall.
A key step in MET is the establishment of apical/basolateral polarity, which is mediated by polarity complexes such as PAR and CRB. This involves the repositioning of organelles and the formation of distinct membrane domains. The cell synthesizes new junctional proteins and reorganizes the cytoskeleton to support this polarity.
Formation of Intercellular Adhesive Junctions
In simple terms: The cell builds connections with neighboring cells to form a tight sheet.
MET requires the formation of intercellular adhesive junctions, including tight junctions, adherens junctions, and desmosomes. E-cadherin (CDH1) is a major component of adherens junctions and is upregulated during MET. Tight junction proteins such as ZO-1 (TJP1) and occludin are also assembled, creating a barrier between apical and basolateral compartments.
Synthesis of Basement Membrane Components
In simple terms: The cell produces a supportive mat underneath itself.
Epithelial cells synthesize and deposit basement membrane components, including laminins, collagen IV, and nidogen. This basement membrane provides structural support and signals that reinforce the epithelial phenotype. The deposition of these components is a hallmark of MET and is essential for tissue organization.
Completion of Epithelial Differentiation
In simple terms: The cell is now a full epithelial cell.
The final stage of MET involves the full acquisition of epithelial characteristics, including apical microvilli, polarized secretion, and the expression of epithelial-specific genes such as cytokeratins. The cell becomes integrated into an epithelial sheet and loses mesenchymal markers. This transition is often accompanied by changes in cell cycle regulation and metabolic reprogramming.
Key Genes Involved in GO:0060231 mesenchymal to epithelial transition
The following genes and proteins are key players in mesenchymal to epithelial transition (MET), based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CDH1 | E-cadherin, core adherens junction protein upregulated during MET | Marker of MET; loss is associated with EMT and cancer progression |
| TJP1 | Tight junction protein ZO-1, essential for epithelial barrier formation | Marker of epithelial polarity; studied in MET and cancer |
| VIM | Vimentin, mesenchymal intermediate filament downregulated during MET | Marker of mesenchymal state; its loss indicates MET |
| CDH2 | N-cadherin, mesenchymal adhesion molecule downregulated during MET | Marker of mesenchymal phenotype; switch to CDH1 is key in MET |
| FN1 | Fibronectin, extracellular matrix protein secreted by mesenchymal cells | Downregulated during MET; involved in cell migration |
| LAMA1 | Laminin subunit alpha-1, basement membrane component | Upregulated during MET; supports epithelial polarity |
| COL4A1 | Collagen type IV alpha-1, basement membrane component | Synthesized during MET; marker of epithelial differentiation |
| TGFB1 | Transforming growth factor beta-1, induces EMT and inhibits MET | Key regulator of MET/EMT balance; therapeutic target |
| SNAI1 | Snail family transcriptional repressor 1, induces EMT | Inhibits MET by repressing E-cadherin; studied in cancer |
| SNAI2 | Slug, transcriptional repressor that promotes EMT | Inhibits MET; associated with metastasis |
| TWIST1 | Transcription factor that promotes EMT | Inhibits MET; involved in cancer progression |
| ZEB1 | Zinc finger E-box binding homeobox 1, EMT inducer | Represses E-cadherin; inhibits MET |
| ZEB2 | Zinc finger E-box binding homeobox 2, EMT inducer | Represses E-cadherin; inhibits MET |
| CTNNB1 | Beta-catenin, adherens junction protein and transcriptional regulator | Involved in MET-associated signaling; mutations in cancer |
| KRT8 | Keratin 8, epithelial intermediate filament | Upregulated during MET; marker of epithelial cells |
| KRT18 | Keratin 18, epithelial intermediate filament | Upregulated during MET; marker of epithelial cells |
| OCLN | Occludin, tight junction protein | Upregulated during MET; essential for epithelial barrier |
| EPCAM | Epithelial cell adhesion molecule | Upregulated during MET; marker of epithelial cells |
How Is mesenchymal to epithelial transition Regulated?
MET is regulated by a complex network of signaling pathways and transcription factors. TGF-beta signaling is a major inducer of EMT and can inhibit MET, while BMP signaling can promote MET in certain contexts. Transcription factors such as SNAI1, SNAI2, TWIST1, ZEB1, and ZEB2 repress E-cadherin and promote EMT, thereby inhibiting MET. Conversely, factors that promote epithelial differentiation, such as GRHL2 and ELF3, can drive MET. The balance between these regulators determines cell fate and is influenced by the extracellular matrix, growth factors, and microRNAs.
mesenchymal to epithelial transition and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CDH1 | Cancer metastasis, hereditary diffuse gastric cancer | Knockout or knock-in in cancer cell lines; organoids |
| TGFB1 | Fibrosis, cancer progression | Overexpression or knockout in fibroblasts; mouse models |
| SNAI1 | Breast cancer metastasis | Knockout in breast cancer cells; xenograft models |
| ZEB1 | Pancreatic cancer, metastasis | Knockout in pancreatic cancer cells; organoids |
| VIM | Cancer EMT/MET balance | Knockout in mesenchymal cells; migration assays |
MET in Cancer Metastasis
In cancer, MET is critical for metastatic colonization: disseminated mesenchymal tumor cells that undergo MET can form epithelial-like secondary tumors at distant sites. This process is observed in breast, pancreatic, and other carcinomas, where MET enables cancer cells to adapt to new microenvironments. Targeting MET pathways could prevent metastatic outgrowth.
MET in Fibrosis and Tissue Repair
MET is involved in tissue repair and fibrosis, where epithelial regeneration requires the transition of mesenchymal cells to epithelial cells. In renal fibrosis, EMT contributes to fibrosis, and MET may reverse this process. Understanding MET in fibrosis could lead to therapies that promote tissue regeneration.
MET in Development and Developmental Disorders
MET is essential for embryonic development, including the epithelialization of the lateral plate mesoderm and the formation of somites and kidney tubules. Disruption of MET can lead to developmental abnormalities, although specific human disorders are still being characterized.
From mesenchymal to epithelial transition-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of a candidate gene induce MET? | CRISPR knockout in mesenchymal cell lines (e.g., MDA-MB-231) |
| Does a point mutation in CDH1 affect MET? | CRISPR point mutation knock-in in epithelial cells |
| Does overexpression of a transcription factor drive MET? | CRISPR overexpression (e.g., dCas9-VP64) in mesenchymal cells |
| How does a tagged protein localize during MET? | Knock-in of fluorescent tag (e.g., GFP) at endogenous locus |
| What is the transcriptional profile during MET? | RNA-seq of cells undergoing MET after CRISPR perturbation |
| Can MET be monitored in real time? | Live-cell imaging of junctional markers in knock-in reporter lines |
How to Study the mesenchymal to epithelial transition Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify MET-associated transcriptional programs |
| Proteomics | Protein abundance and modifications | Quantify junctional and polarity proteins |
| Immunofluorescence | Localization of polarity and junction markers | Visualize MET in cells and tissues |
| Live-cell imaging | Dynamic changes in cell morphology and junctions | Track MET over time |
| Migration assay | Cell motility | Assess loss of mesenchymal phenotype |
| Adhesion assay | Cell-cell adhesion strength | Measure epithelial junction formation |
| CRISPR screen | Identify genes required for MET | Functional genomics of MET regulators |
| Flow cytometry | Surface marker expression (e.g., EPCAM) | Quantify MET in heterogeneous populations |
Transcriptomic Analysis (RNA-seq)
RNA-seq is used to profile gene expression changes during MET, identifying upregulated epithelial genes and downregulated mesenchymal genes. This method can reveal regulatory networks and alternative splicing events.
Proteomic and Phosphoproteomic Analysis
Mass spectrometry-based proteomics can quantify protein abundance and post-translational modifications during MET, providing insights into signaling pathways and junctional complex assembly.
Imaging and Morphological Assays
Immunofluorescence and live-cell imaging are used to visualize polarity markers, junction formation, and cytoskeletal reorganization during MET. These methods confirm the transition at the cellular level.
Functional Assays
Migration, invasion, and adhesion assays measure the functional consequences of MET, such as decreased motility and increased cell-cell adhesion. These assays are often combined with CRISPR perturbations.
How CRISPR Can Be Used to Study GO:0060231 mesenchymal to epithelial transition
Knockout
CRISPR knockout is used to delete candidate MET regulators, such as CDH1 or TJP1, to test their requirement for the transition. Knockout of mesenchymal genes like VIM can also induce MET-like changes.
Point Mutation
Point mutations can be introduced into genes like CDH1 to model cancer-associated variants and study their impact on MET. This approach helps dissect the functional consequences of specific alleles.
Knock-in
Knock-in of fluorescent tags (e.g., GFP) at endogenous loci allows real-time tracking of MET markers such as E-cadherin. Knock-in of conditional alleles enables tissue-specific studies.
Overexpression
CRISPR activation (CRISPRa) or cDNA overexpression can drive expression of MET-promoting factors, such as GRHL2, to induce MET in mesenchymal cells. This helps identify sufficiency of individual genes.
How EDITGENE Supports mesenchymal to epithelial transition Research
Researchers studying mesenchymal to epithelial transition-related genes often need to determine whether a candidate gene is causally involved in the transition or is merely a bystander. CRISPR-based models provide a robust way to test gene function in relevant cell types.
Contact EDITGENE today to design your custom CRISPR model for mesenchymal to epithelial transition research.
Frequently Asked Questions About mesenchymal to epithelial transition
What is mesenchymal to epithelial transition (MET)?
MET is the biological process (GO:0060231) where a mesenchymal cell becomes an epithelial cell by gaining polarity, forming adhesive junctions, and synthesizing basement membrane components.
What genes are involved in mesenchymal to epithelial transition?
Key genes include CDH1 (E-cadherin), TJP1 (ZO-1), VIM, CDH2, and transcription factors like SNAI1, ZEB1, and TWIST1.
How is MET different from EMT?
MET is the reverse of EMT: MET converts mesenchymal cells to epithelial cells, while EMT converts epithelial cells to mesenchymal cells.
Why is MET important in cancer?
MET allows disseminated mesenchymal cancer cells to colonize distant organs and form epithelial-like metastases, contributing to cancer progression.
What are the hallmarks of MET?
Hallmarks include apical/basolateral polarity, formation of tight and adherens junctions, upregulation of E-cadherin, and deposition of basement membrane components.
How can I study MET in the lab?
Common methods include RNA-seq, proteomics, immunofluorescence, live-cell imaging, and CRISPR-based perturbations.
What signaling pathways regulate MET?
TGF-beta signaling inhibits MET, while BMP signaling can promote it; transcription factors like SNAI1 and ZEB1 repress epithelial genes.
Can CRISPR be used to study MET?
Yes, CRISPR knockout, knock-in, point mutation, and overexpression models are widely used to dissect MET gene function.
What diseases are associated with MET dysregulation?
Cancer metastasis, fibrosis, and developmental disorders have been linked to abnormal MET.
What cell models are used for MET research?
Mesenchymal cell lines (e.g., MDA-MB-231) and epithelial cell lines (e.g., MCF-7) are commonly used, along with organoids and primary cells.
Conclusion
Mesenchymal to epithelial transition (GO:0060231) is a fundamental biological process that reverses EMT and is essential for development, tissue repair, and cancer metastasis. Understanding its molecular mechanisms and regulatory networks can provide insights into disease pathogenesis and identify new therapeutic targets. CRISPR-based models and multi-omics approaches are powerful tools for dissecting MET and its roles in health and disease.
References
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- 3. Sannino G et al.. 2017. Epithelial-to-Mesenchymal and Mesenchymal-to-Epithelial Transition in Mesenchymal Tumors: A Paradox in Sarcomas?. Cancer Res 77(17):4556-4561 PMID: 28811330
- 4. Chaffer CL et al.. 2007. Mesenchymal to epithelial transition in development and disease.. Cells Tissues Organs 185(1-3):7-19 PMID: 17587803
- 5. Tomaskovic-Crook E et al.. 2009. Epithelial to mesenchymal transition and breast cancer.. Breast Cancer Res 11(6):213 PMID: 19909494
- 6. Cano CE et al.. 2010. Epithelial-to-mesenchymal transition in pancreatic adenocarcinoma.. ScientificWorldJournal 10:1947-57 PMID: 20890584
- 7. Zeisberg M et al.. 2004. The role of epithelial-to-mesenchymal transition in renal fibrosis.. J Mol Med (Berl) 82(3):175-81 PMID: 14752606
