Details for: TWIST1

Gene ID: 7291

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: TWIST1

Ensembl ID: ENSG00000122691

Description: twist family bHLH transcription factor 1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

  • Cytokine signaling in immune system
    (R-HSA-1280215)
  • Disease
    (R-HSA-1643685)
  • Diseases of signal transduction by growth factor receptors and second messengers
    (R-HSA-5663202)
  • Gene expression (transcription)
    (R-HSA-74160)
  • Generic transcription pathway
    (R-HSA-212436)
  • Immune system
    (R-HSA-168256)
  • Interleukin-4 and interleukin-13 signaling
    (R-HSA-6785807)
  • Nuclear events stimulated by alk signaling in cancer
    (R-HSA-9725371)
  • Regulation of runx2 expression and activity
    (R-HSA-8939902)
  • Rna polymerase ii transcription
    (R-HSA-73857)
  • Signaling by alk fusions and activated point mutants
    (R-HSA-9725370)
  • Signaling by alk in cancer
    (R-HSA-9700206)
  • Signaling by interleukins
    (R-HSA-449147)
  • Transcriptional regulation by runx2
    (R-HSA-8878166)
  • Aortic valve morphogenesis
    (GO:0003180)
  • Bhlh transcription factor binding
    (GO:0043425)
  • Cardiac neural crest cell migration involved in outflow tract morphogenesis
    (GO:0003253)
  • Cell proliferation involved in heart valve development
    (GO:2000793)
  • Cellular response to growth factor stimulus
    (GO:0071363)
  • Cellular response to hypoxia
    (GO:0071456)
  • Chromatin
    (GO:0000785)
  • Cis-regulatory region sequence-specific dna binding
    (GO:0000987)
  • Cranial suture morphogenesis
    (GO:0060363)
  • Developmental process
    (GO:0032502)
  • Dna-binding transcription factor activity, rna polymerase ii-specific
    (GO:0000981)
  • Dna-binding transcription factor binding
    (GO:0140297)
  • Dna-binding transcription repressor activity
    (GO:0001217)
  • E-box binding
    (GO:0070888)
  • Embryonic camera-type eye formation
    (GO:0060900)
  • Embryonic cranial skeleton morphogenesis
    (GO:0048701)
  • Embryonic digit morphogenesis
    (GO:0042733)
  • Embryonic forelimb morphogenesis
    (GO:0035115)
  • Embryonic hindlimb morphogenesis
    (GO:0035116)
  • Endocardial cushion morphogenesis
    (GO:0003203)
  • Energy homeostasis
    (GO:0097009)
  • Eyelid development in camera-type eye
    (GO:0061029)
  • Histone deacetylase binding
    (GO:0042826)
  • In utero embryonic development
    (GO:0001701)
  • Mitral valve morphogenesis
    (GO:0003183)
  • Muscle organ development
    (GO:0007517)
  • Negative regulation of apoptotic process
    (GO:0043066)
  • Negative regulation of cellular senescence
    (GO:2000773)
  • Negative regulation of dna-templated transcription
    (GO:0045892)
  • Negative regulation of dna damage response, signal transduction by p53 class mediator
    (GO:0043518)
  • Negative regulation of double-strand break repair
    (GO:2000780)
  • Negative regulation of macrophage cytokine production
    (GO:0010936)
  • Negative regulation of mirna transcription
    (GO:1902894)
  • Negative regulation of osteoblast differentiation
    (GO:0045668)
  • Negative regulation of peroxisome proliferator activated receptor signaling pathway
    (GO:0035359)
  • Negative regulation of phosphatidylinositol 3-kinase/protein kinase b signal transduction
    (GO:0051898)
  • Negative regulation of skeletal muscle tissue development
    (GO:0048642)
  • Negative regulation of striated muscle tissue development
    (GO:0045843)
  • Negative regulation of transcription by rna polymerase ii
    (GO:0000122)
  • Negative regulation of tumor necrosis factor production
    (GO:0032720)
  • Neural tube closure
    (GO:0001843)
  • Neuron migration
    (GO:0001764)
  • Nucleoplasm
    (GO:0005654)
  • Nucleus
    (GO:0005634)
  • Ossification
    (GO:0001503)
  • Osteoblast differentiation
    (GO:0001649)
  • Outer ear morphogenesis
    (GO:0042473)
  • Positive regulation of angiogenesis
    (GO:0045766)
  • Positive regulation of cell migration
    (GO:0030335)
  • Positive regulation of cell motility
    (GO:2000147)
  • Positive regulation of dna-templated transcription initiation
    (GO:2000144)
  • Positive regulation of endocardial cushion to mesenchymal transition involved in heart valve formation
    (GO:2000802)
  • Positive regulation of epithelial cell proliferation
    (GO:0050679)
  • Positive regulation of epithelial to mesenchymal transition
    (GO:0010718)
  • Positive regulation of fatty acid beta-oxidation
    (GO:0032000)
  • Positive regulation of gene expression
    (GO:0010628)
  • Positive regulation of interleukin-6 production
    (GO:0032755)
  • Positive regulation of monocyte chemotactic protein-1 production
    (GO:0071639)
  • Positive regulation of transcription by rna polymerase ii
    (GO:0045944)
  • Positive regulation of transcription regulatory region dna binding
    (GO:2000679)
  • Positive regulation of tumor necrosis factor production
    (GO:0032760)
  • Protein binding
    (GO:0005515)
  • Protein domain specific binding
    (GO:0019904)
  • Protein homodimerization activity
    (GO:0042803)
  • Regulation of bone mineralization
    (GO:0030500)
  • Regulation of transcription by rna polymerase ii
    (GO:0006357)
  • Rhythmic process
    (GO:0048511)
  • Rna polymerase ii transcription regulatory region sequence-specific dna binding
    (GO:0000977)
  • Roof of mouth development
    (GO:0060021)
  • Transcription coregulator binding
    (GO:0001221)

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • skin fibroblast CL0002620
    CSI 21.35
    rCSI 18.4%
    PRS 93.35
  • bronchus fibroblast of lung CL2000093
    CSI 9.8
    rCSI 7.96%
    PRS 93.52
  • cerebral cortex endothelial cell CL1001602
    CSI 3.85
    rCSI 6.66%
    PRS 90.2
  • pericyte CL0000669
    CSI 2.98
    rCSI 7.95%
    PRS 73.42
  • adipocyte CL0000136
    CSI 2.98
    rCSI 3.83%
    PRS 87.32
  • perivascular cell CL4033054
    CSI 2.55
    rCSI 3.48%
    PRS 96.16
  • vascular associated smooth muscle cell CL0000359
    CSI 1.98
    rCSI 6.43%
    PRS 92.57
  • vascular leptomeningeal cell CL4023051
    CSI 1.9
    rCSI 3.33%
    PRS 91.71
  • chondrocyte CL0000138
    CSI 1.84
    rCSI 2.93%
    PRS 90.54
  • keratocyte CL0002363
    CSI 1.61
    rCSI 3.86%
    PRS 94.33
  • retinal ganglion cell CL0000740
    CSI 1.6
    rCSI 3.54%
    PRS 85.93
  • Hofbauer cell CL3000001
    CSI 1.53
    rCSI 2.88%
    PRS 96.95
  • fibroblast of breast CL4006000
    CSI 1.35
    rCSI 5.66%
    PRS 95.5
  • basal cell of epidermis CL0002187
    CSI 1.33
    rCSI 2.35%
    PRS 68.71
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 1.17
    rCSI 4.19%
    PRS 82.73
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 1.14
    rCSI 1.38%
    PRS 76.64
  • L6b glutamatergic cortical neuron CL4023038
    CSI 0.99
    rCSI 3.09%
    PRS 85.49
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 0.93
    rCSI 2.25%
    PRS 82.46
  • mesenchymal cell CL0008019
    CSI 0.89
    rCSI 2.27%
    PRS 90.26
  • microcirculation associated smooth muscle cell CL0008035
    CSI 0.81
    rCSI 2.33%
    PRS 93.31
  • pancreatic stellate cell CL0002410
    CSI 0.73
    rCSI 4.23%
    PRS 94.96
  • blood vessel smooth muscle cell CL0019018
    CSI 0.37
    rCSI 2.99%
    PRS 92.6
  • mesenchymal stem cell CL0000134
    CSI 0.22
    rCSI 2.36%
    PRS 95.07

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [TWIST1](/details-gene/7291) (twist family bHLH transcription factor 1) is a protein-coding gene located on chromosome 7p21.1 that encodes a basic helix-loop-helix (bHLH) transcription factor. This protein plays a fundamental role in embryonic development, particularly in the morphogenesis of mesodermally-derived tissues [Link](https://doi.org/10.1016/s0378-1119(96)00727-5). Consistent with this developmental origin, its expression in adult tissues is highly significant in mesenchymal cell types, most notably in [skin fibroblast](/details-cell/CL0002620) and [bronchus fibroblast of lung](/details-cell/CL2000093). Functionally, [TWIST1](/details-gene/7291) acts as a transcriptional regulator, binding to E-box sequences to control gene expression involved in cell lineage determination and differentiation. Its critical role in development is underscored by its clinical association with several congenital syndromes, including Saethre-Chotzen syndrome ([180750](https://omim.org/entry/180750)), which is characterized by craniosynostosis and limb abnormalities resulting from mutations in the [TWIST1](/details-gene/7291) gene [Link](https://doi.org/10.1038/ng0197-36), [Link](https://doi.org/10.1038/ng0197-42). ## Cellular Roles and Expression Landscape The expression profile of [TWIST1](/details-gene/7291) highlights its central role in defining and maintaining the phenotype of stromal and mesenchymal cell populations. **Overall**, the gene shows its highest significance in [skin fibroblast](/details-cell/CL0002620) (CSI: 21.35) and other fibroblast subtypes, such as [bronchus fibroblast of lung](/details-cell/CL2000093) (CSI: 9.80). This pattern extends to related mesenchymal and stromal cells, including [pericyte](/details-cell/CL0000669), [adipocyte](/details-cell/CL0000136), and [vascular associated smooth muscle cell](/details-cell/CL0000359), where it also demonstrates significant expression. This strong and specific expression signature suggests that [TWIST1](/details-gene/7291) is a key transcriptional regulator essential for the core identity and function of these structural and connective tissue cells throughout the body. Its involvement in these cell types is consistent with its known functions in tissue morphogenesis and repair. ## Pathways and Molecular Function [TWIST1](/details-gene/7291) functions primarily as a DNA-binding transcription factor located in the [nucleus](/details-cell/GO:0005634) and associated with [chromatin](/details-cell/GO:0000785). Its molecular activity involves binding to specific DNA sequences known as E-boxes ([GO:0070888](https://www.ebi.ac.uk/QuickGO/term/GO:0070888)), typically forming homodimers or heterodimers with other bHLH proteins to regulate transcription. The biological processes governed by [TWIST1](/details-gene/7291) are heavily skewed towards embryonic development and morphogenesis. It is critically involved in processes such as [ossification](/details-cell/GO:0001503), [cranial suture morphogenesis](/details-cell/GO:0060363), and the development of cardiac structures like the aortic and mitral valves ([GO:0003180](https://www.ebi.ac.uk/QuickGO/term/GO:0003180), [GO:0003183](https://www.ebi.ac.uk/QuickGO/term/GO:0003183)). This aligns perfectly with its clinical association with developmental disorders affecting the skeleton and heart [Link](https://doi.org/10.1007/s00246-015-1202-9). Beyond development, [TWIST1](/details-gene/7291) is a master regulator of cellular plasticity, most notably through its role in promoting [epithelial to mesenchymal transition (EMT)](/details-cell/GO:0010718). This process is crucial not only during embryogenesis but also in pathological contexts like cancer metastasis. It also positively regulates cell migration ([GO:0030335](https://www.ebi.ac.uk/QuickGO/term/GO:0030335)) and angiogenesis ([GO:0045766](https://www.ebi.ac.uk/QuickGO/term/GO:0045766)). Furthermore, [TWIST1](/details-gene/7291) interfaces with immune signaling pathways ([R-HSA-1280215](https://reactome.org/content/detail/R-HSA-1280215)), where it can act as a negative regulator of cytokine production in immune cells like macrophages ([GO:0010936](https://www.ebi.ac.uk/QuickGO/term/GO:0010936)), a function linked to the repression of NF-kappaB activity [Link](https://doi.org/10.1016/s0092-8674(03)00002-3). ## Research Directions The established role of [TWIST1](/details-gene/7291) in development, EMT, and stromal cell biology suggests several avenues for future research. Its high expression in [fibroblasts](/details-cell/CL0002620) points toward a significant function in tissue homeostasis, fibrosis, and the tumor microenvironment. **Proposed Hypotheses:** 1. Given its function in promoting a mesenchymal state ([GO:0010718](https://www.ebi.ac.uk/QuickGO/term/GO:0010718)) and its high expression in [fibroblasts](/details-cell/CL0002620), [TWIST1](/details-gene/7291) may function as a master regulator of fibroblast-to-myofibroblast differentiation during pathological fibrosis, driving the expression of extracellular matrix components and contractile proteins. 2. Based on its regulatory role in cytokine signaling ([R-HSA-1280215](https://reactome.org/content/detail/R-HSA-1280215)) and its expression in stromal cells, [TWIST1](/details-gene/7291) activation in cancer-associated fibroblasts may create an immunosuppressive tumor microenvironment by directly modulating the secretion of chemokines that exclude or inhibit cytotoxic T lymphocytes. **Experimental Approach:** To test the first hypothesis regarding the role of [TWIST1](/details-gene/7291) in fibrosis, a conditional knockout mouse model (e.g., employing a Fibroblast Activation Protein-Cre driver) could be utilized. Following the induction of fibrosis in an organ like the lung (bleomycin model) or skin (wounding model), the degree of myofibroblast differentiation (assessed by alpha-smooth muscle actin staining) and collagen deposition (assessed by Picrosirius red staining and hydroxyproline assays) would be compared between knockout and wild-type animals. RNA-sequencing of isolated fibroblasts from these models would further clarify the downstream transcriptional programs controlled by [TWIST1](/details-gene/7291) during fibrotic activation. **Therapeutic Potential:** As a transcription factor, [TWIST1](/details-gene/7291) is a challenging therapeutic target for direct small molecule inhibition. However, its pivotal role in driving cancer cell invasion and metastasis makes it a high-priority target in oncology. Therapeutic strategies are more likely to succeed by targeting its functional activity indirectly. This could involve developing molecules that disrupt its dimerization with essential partners or that inhibit key downstream effector proteins responsible for its pro-metastatic functions. Given its role as a driver of malignancy and fibrosis, therapeutic intervention would focus on **inhibition** rather than activation.

Genular Protein ID: 2344616009

Symbol: TWST1_HUMAN

Name: Twist-related protein 1

UniProtKB Accession Codes:

Q15672 A4D128 Q92487 Q99804

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CORUM 1 CTD 1 ChiTaRS 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 7 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 69 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 IDEAL 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 9 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 3 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PIR 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 4 RefSeq 2 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 9073070

Title: Cloning of the human twist gene: its expression is retained in adult mesodermally-derived tissues.

PubMed ID: 9073070

DOI: 10.1016/s0378-1119(96)00727-5

PubMed ID: 8995765

Title: The human H-twist gene is located at 7p21 and encodes a B-HLH protein that is 96% similar to its murine M-twist counterpart.

PubMed ID: 8995765

DOI: 10.1007/s003359900269

PubMed ID: 8988166

Title: Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome.

PubMed ID: 8988166

DOI: 10.1038/ng0197-36

PubMed ID: 9215678

Title: Translocation breakpoint maps 5 kb 3-prime from TWIST in a patient affected with Saethre-Chotzen syndrome.

PubMed ID: 9215678

DOI: 10.1093/hmg/6.7.1079

PubMed ID: 12853948

Title: The DNA sequence of human chromosome 7.

PubMed ID: 12853948

DOI: 10.1038/nature01782

PubMed ID: 12690205

Title: Human chromosome 7: DNA sequence and biology.

PubMed ID: 12690205

DOI: 10.1126/science.1083423

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 12553906

Title: Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity.

PubMed ID: 12553906

DOI: 10.1016/s0092-8674(03)00002-3

PubMed ID: 8988167

Title: Mutations of the TWIST gene in the Saethre-Chotzen syndrome.

PubMed ID: 8988167

DOI: 10.1038/ng0197-42

PubMed ID: 10465122

Title: Identification of a frameshift mutation in the gene TWIST in a family affected with Robinow-Sorauf syndrome.

PubMed ID: 10465122

PubMed ID: 11754069

Title: Another TWIST on Baller-Gerold syndrome.

PubMed ID: 11754069

DOI: 10.1002/ajmg.10065

PubMed ID: 17343269

Title: Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations.

PubMed ID: 17343269

DOI: 10.1002/ajmg.a.31630

PubMed ID: 25981568

Title: Functional analysis of two novel mutations in TWIST1 protein motifs found in ventricular septal defect patients.

PubMed ID: 25981568

DOI: 10.1007/s00246-015-1202-9

PubMed ID: 28369379

Title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.

PubMed ID: 28369379

DOI: 10.1093/hmg/ddx107

Sequence Information:

  • Length: 202
  • Mass: 20954
  • Checksum: 9394E4351BA1D081
  • Sequence:
    • MMQDVSSSPV SPADDSLSNS EEEPDRQQPP SGKRGGRKRR SSRRSAGGGA GPGGAAGGGV 
GGGDEPGSPA QGKRGKKSAG CGGGGGAGGG GGSSSGGGSP QSYEELQTQR VMANVRERQR 
TQSLNEAFAA LRKIIPTLPS DKLSKIQTLK LAARYIDFLY QVLQSDELDS KMASCSYVAH 
ERLSYAFSVW RMEGAWSMSA SH