Details for: SIX5

Gene ID: 147912

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: SIX5

Ensembl ID: ENSG00000177045

Description: SIX homeobox 5

Cell Significance Landscape

Associated with

  • Chromatin
    (GO:0000785)
  • Cytosol
    (GO:0005829)
  • Dna-binding transcription activator activity, rna polymerase ii-specific
    (GO:0001228)
  • Dna-binding transcription factor activity, rna polymerase ii-specific
    (GO:0000981)
  • Golgi apparatus
    (GO:0005794)
  • Intracellular membrane-bounded organelle
    (GO:0043231)
  • Lens development in camera-type eye
    (GO:0002088)
  • Leydig cell proliferation
    (GO:0160024)
  • Negative regulation of dna-templated transcription
    (GO:0045892)
  • Negative regulation of skeletal muscle satellite cell proliferation
    (GO:1902723)
  • Nucleoplasm
    (GO:0005654)
  • Nucleus
    (GO:0005634)
  • Positive regulation of transcription by rna polymerase ii
    (GO:0045944)
  • Protein binding
    (GO:0005515)
  • Regulation of transcription by rna polymerase ii
    (GO:0006357)
  • Rna polymerase ii cis-regulatory region sequence-specific dna binding
    (GO:0000978)
  • Spermatid development
    (GO:0007286)
  • Transcription regulator complex
    (GO:0005667)

Significant Cells

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

  • bronchus fibroblast of lung CL2000093
    CSI 3.81
    rCSI 3.1%
    PRS 99.57
  • ependymal cell CL0000065
    CSI 2.99
    rCSI 6.06%
    PRS 95.88
  • extravillous trophoblast CL0008036
    CSI 2.87
    rCSI 3.55%
    PRS 98.95
  • astrocyte of the cerebral cortex CL0002605
    CSI 1.78
    rCSI 3.98%
    PRS 97.91

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.

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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 [SIX5](/details-gene/147912) (SIX homeobox 5) is a protein-coding gene located on chromosome 19q13.32 that encodes a homeodomain-containing transcription factor. As a DNA-binding protein, [SIX5](/details-gene/147912) functions as a regulator of transcription by RNA polymerase II, capable of both activation and repression of target genes. It plays a significant role in various developmental processes, most notably in the development of the lens, muscle, and male reproductive system. **Overall**, expression data indicate that [SIX5](/details-gene/147912) is a significant marker for specialized cell types, including [bronchus fibroblast of lung](/details-cell/CL2000093), glial cells like [ependymal cell](/details-cell/CL0000065), and [extravillous trophoblast](/details-cell/CL0008036). Clinically, mutations in [SIX5](/details-gene/147912) have been identified as a cause of Branchio-oto-renal syndrome ([Link](https://doi.org/10.1086/513322)), and the gene has also been historically studied for its proximity to the unstable repeat expansion associated with myotonic dystrophy ([Link](https://doi.org/10.1093/hmg/4.10.1919)). ## Cellular Roles and Expression Landscape The expression profile of [SIX5](/details-gene/147912) suggests a specialized function in distinct structural, neuro-supportive, and developmental cell lineages, rather than a ubiquitous role. **Overall**, the gene demonstrates its highest significance in [bronchus fibroblast of lung](/details-cell/CL2000093) (CSI: 3.81), indicating a potential function in the maintenance of lung connective tissue and extracellular matrix homeostasis. Its notable expression in glial cell populations, including [ependymal cell](/details-cell/CL0000065) (CSI: 2.99) and [astrocyte of the cerebral cortex](/details-cell/CL0002605) (CSI: 1.78), points towards a role in the development or function of the central nervous system's support structures. Furthermore, its high significance in [extravillous trophoblast](/details-cell/CL0008036) (CSI: 2.87) is consistent with a role during placentation and embryonic development. This diverse but specific expression pattern aligns with its established involvement in organogenesis, such as eye development ([Link](https://doi.org/10.1093/hmg/8.3.481)) and the regulation of muscle precursor cells during somitogenesis ([Link](https://doi.org/10.1023/a:1020990825644)). ## Pathways and Molecular Function [SIX5](/details-gene/147912) operates as a sequence-specific, DNA-binding transcription factor. Its primary molecular function ([GO:0000981](https://www.ebi.ac.uk/QuickGO/term/GO:0000981)) is to modulate gene expression by binding to cis-regulatory regions of target genes and recruiting the RNA polymerase II machinery. Functional studies and annotations suggest it can act as both a transcriptional activator ([GO:0001228](https://www.ebi.ac.uk/QuickGO/term/GO:0001228)) and a repressor ([GO:0045892](https://www.ebi.ac.uk/QuickGO/term/GO:0045892)), indicating its role is context-dependent. Consistent with its function, the [SIX5](/details-gene/147912) protein is localized to the [nucleus](/details-cell/GO:0005634), where it is found associated with [chromatin](/details-cell/GO:0000785) and as a component of [transcription regulator complexes](/details-cell/GO:0005667). Through this regulatory activity, [SIX5](/details-gene/147912) directs key biological processes. It is essential for [lens development in camera-type eye](/details-cell/GO:0002088) ([Link](https://doi.org/10.1093/hmg/8.3.481)) and is involved in male reproductive development, including [spermatid development](/details-cell/GO:0007286) and [Leydig cell proliferation](/details-cell/GO:0160024). Additionally, it participates in myogenesis by contributing to the [negative regulation of skeletal muscle satellite cell proliferation](/details-cell/GO:1902723), a role consistent with its expression during embryonic development ([Link](https://doi.org/10.1023/a:1020990825644)). ## Research Directions The specific expression pattern of [SIX5](/details-gene/147912) and its role as a developmental transcription factor provide several avenues for future research, particularly in connecting its cellular functions to human disease. **Testable Hypotheses:** 1. Given its high significance in [bronchus fibroblast of lung](/details-cell/CL2000093), dysregulation of [SIX5](/details-gene/147912) may contribute to the pathology of fibrotic lung diseases. It is hypothesized that [SIX5](/details-gene/147912) regulates the expression of key extracellular matrix genes in response to pro-fibrotic stimuli, and its altered activity could promote excessive tissue remodeling. 2. The loss-of-function mutations in [SIX5](/details-gene/147912) that cause Branchio-oto-renal syndrome ([OMIM [600963](https://omim.org/entry/600963)]) likely disrupt a critical developmental gene regulatory network. It is hypothesized that [SIX5](/details-gene/147912) is an upstream regulator of other transcription factors and signaling molecules essential for the proper formation of the branchial arches, otic vesicle, and kidneys during embryogenesis. 3. The expression of [SIX5](/details-gene/147912) in [astrocytes](/details-cell/CL0002605) and [ependymal cells](/details-cell/CL0000065) suggests a role in central nervous system homeostasis. It is hypothesized that [SIX5](/details-gene/147912) is involved in maintaining the integrity of the blood-brain barrier or regulating glial responses to injury, and its misexpression could be a contributing factor in certain neurodevelopmental or neurodegenerative disorders. **Proposed Experiment:** To test the hypothesis that [SIX5](/details-gene/147912) regulates lung fibroblast activity (Hypothesis 1), a compelling approach would be to use CRISPR-Cas9 to knock down [SIX5](/details-gene/147912) in primary human lung fibroblasts. These modified cells, along with control cells, could then be stimulated with the pro-fibrotic cytokine TGF-β. The functional consequences would be assessed through RNA-sequencing to identify [SIX5](/details-gene/147912)-dependent changes in the transcriptome, focusing on genes encoding collagens, fibronectin, and metalloproteinases. Concurrently, functional assays such as collagen gel contraction and cell migration assays would directly measure the impact of [SIX5](/details-gene/147912) loss on key cellular behaviors associated with fibrosis. **Therapeutic Potential:** As a nuclear transcription factor, [SIX5](/details-gene/147912) represents a challenging therapeutic target for direct small molecule modulation. The primary associated pathology, Branchio-oto-renal syndrome, is a developmental disorder resulting from haploinsufficiency ([Link](https://doi.org/10.1086/513322)). Therefore, a therapeutic strategy would logically involve **activation** of the remaining functional allele or a form of gene replacement therapy, rather than inhibition. Such approaches remain highly experimental. A more near-term strategy might involve targeting the downstream pathways that are dysregulated by [SIX5](/details-gene/147912) deficiency, which could offer an indirect but more tractable therapeutic avenue.

Genular Protein ID: 412562649

Symbol: SIX5_HUMAN

Name: Homeobox protein SIX5

UniProtKB Accession Codes:

Q8N196

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 5 Ensembl 1 ExpressionAtlas 1 GO 16 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 RefSeq 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 8595416

Title: A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat.

PubMed ID: 8595416

DOI: 10.1093/hmg/4.10.1919

PubMed ID: 15057824

Title: The DNA sequence and biology of human chromosome 19.

PubMed ID: 15057824

DOI: 10.1038/nature02399

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: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 9949207

Title: Characterization of the expression of DMPK and SIX5 in the human eye and implications for pathogenesis in myotonic dystrophy.

PubMed ID: 9949207

DOI: 10.1093/hmg/8.3.481

PubMed ID: 10756185

Title: Functional analysis of the homeodomain protein SIX5.

PubMed ID: 10756185

DOI: 10.1093/nar/28.9.1871

PubMed ID: 12500905

Title: Six and Eya expression during human somitogenesis and MyoD gene family activation.

PubMed ID: 12500905

DOI: 10.1023/a:1020990825644

PubMed ID: 17357085

Title: Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.

PubMed ID: 17357085

DOI: 10.1086/513322

Sequence Information:

  • Length: 739
  • Mass: 74562
  • Checksum: D8A2E8DBBBA263A2
  • Sequence:
    • MATLPAEPSA GPAAGGEAVA AAAATEEEEE EARQLLQTLQ AAEGEAAAAA GAGAGAAAAG 
AEGPGSPGVP GSPPEAASEP PTGLRFSPEQ VACVCEALLQ AGHAGRLSRF LGALPPAERL 
RGSDPVLRAR ALVAFQRGEY AELYRLLESR PFPAAHHAFL QDLYLRARYH EAERARGRAL 
GAVDKYRLRK KFPLPKTIWD GEETVYCFKE RSRAALKACY RGNRYPTPDE KRRLATLTGL 
SLTQVSNWFK NRRQRDRTGA GGGAPCKSES DGNPTTEDES SRSPEDLERG AAPVSAEAAA 
QGSIFLAGTG PPAPCPASSS ILVNGSFLAA SGSPAVLLNG GPVIINGLAL GEASSLGPLL 
LTGGGGAPPP QPSPQGASET KTSLVLDPQT GEVRLEEAQS EAPETKGAQV AAPGPALGEE 
VLGPLAQVVP GPPTAATFPL PPGPVPAVAA PQVVPLSPPP GYPTGLSPTS PLLNLPQVVP 
TSQVVTLPQA VGPLQLLAAG PGSPVKVAAA AGPANVHLIN SGVGVTALQL PSATAPGNFL 
LANPVSGSPI VTGVALQQGK IILTATFPTS MLVSQVLPPA PGLALPLKPE TAISVPEGGL 
PVAPSPALPE AHALGTLSAQ QPPPAAATTS STSLPFSPDS PGLLPNFPAP PPEGLMLSPA 
AVPVWSAGLE LSAGTEGLLE AEKGLGTQAP HTVLRLPDPD PEGLLLGATA GGEVDEGLEA 
EAKVLTQLQS VPVEEPLEL