Details for: SIX4

Gene ID: 51804

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: SIX4

Ensembl ID: ENSG00000100625

Description: SIX homeobox 4

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

  • Anatomical structure morphogenesis
    (GO:0009653)
  • Chromatin
    (GO:0000785)
  • Cytoplasm
    (GO:0005737)
  • Dna-binding transcription activator activity, rna polymerase ii-specific
    (GO:0001228)
  • Dna-binding transcription factor activity, rna polymerase ii-specific
    (GO:0000981)
  • Embryonic cranial skeleton morphogenesis
    (GO:0048701)
  • Fungiform papilla morphogenesis
    (GO:0061197)
  • Generation of neurons
    (GO:0048699)
  • Inner ear morphogenesis
    (GO:0042472)
  • Male gonad development
    (GO:0008584)
  • Male sex determination
    (GO:0030238)
  • Male sex differentiation
    (GO:0046661)
  • Metanephric mesenchyme development
    (GO:0072075)
  • Myoblast migration
    (GO:0051451)
  • Myotome development
    (GO:0061055)
  • Negative regulation of apoptotic process
    (GO:0043066)
  • Negative regulation of dna-templated transcription
    (GO:0045892)
  • Negative regulation of neuron apoptotic process
    (GO:0043524)
  • Negative regulation of satellite cell differentiation
    (GO:1902725)
  • Nucleus
    (GO:0005634)
  • Olfactory placode formation
    (GO:0030910)
  • Pharyngeal system development
    (GO:0060037)
  • Positive regulation of branching involved in ureteric bud morphogenesis
    (GO:0090190)
  • Positive regulation of dna-templated transcription
    (GO:0045893)
  • Positive regulation of transcription by rna polymerase ii
    (GO:0045944)
  • Positive regulation of ureteric bud formation
    (GO:0072107)
  • Protein localization to nucleus
    (GO:0034504)
  • Regulation of branch elongation involved in ureteric bud branching
    (GO:0072095)
  • Regulation of epithelial cell proliferation
    (GO:0050678)
  • Regulation of protein localization
    (GO:0032880)
  • Regulation of synaptic assembly at neuromuscular junction
    (GO:0008582)
  • Regulation of transcription by rna polymerase ii
    (GO:0006357)
  • Rna polymerase ii cis-regulatory region sequence-specific dna binding
    (GO:0000978)
  • Sarcomere organization
    (GO:0045214)
  • Sequence-specific double-stranded dna binding
    (GO:1990837)
  • Skeletal muscle fiber differentiation
    (GO:0098528)
  • Skeletal muscle tissue development
    (GO:0007519)
  • Thymus development
    (GO:0048538)
  • Tongue development
    (GO:0043586)
  • Transcription regulator complex
    (GO:0005667)
  • Trigeminal ganglion development
    (GO:0061551)

Significant Cells

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

  • multi-ciliated epithelial cell CL0005012
    CSI 3.3
    rCSI 3.29%
    PRS 97.09
  • ciliated epithelial cell CL0000067
    CSI 3.19
    rCSI 2.81%
    PRS 96.26
  • lung ciliated cell CL1000271
    CSI 2.51
    rCSI 2.91%
    PRS 97.24
  • ciliated cell CL0000064
    CSI 2.35
    rCSI 3.81%
    PRS 96.47
  • basal cell CL0000646
    CSI 2.19
    rCSI 2.92%
    PRS 98.18
  • ciliated columnar cell of tracheobronchial tree CL0002145
    CSI 1.38
    rCSI 3.14%
    PRS 96.11

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)

Loading network (please wait)...

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 [SIX4](/details-gene/51804) (SIX homeobox 4) is a protein-coding gene located on chromosome 14q23.1 that encodes a DNA-binding transcription factor. As a member of the SIX/sine oculis family, it plays a fundamental role in embryonic development and morphogenesis. Functional annotations implicate [SIX4](/details-gene/51804) in a wide array of developmental processes, including the formation of the cranial skeleton, inner ear, muscle tissue, and nervous system, primarily by regulating transcription from RNA polymerase II promoters. **Overall** expression data highlights its significant and specific role in various types of ciliated epithelial cells, suggesting it is a key regulator for the differentiation, function, or maintenance of these specialized cell lineages. ## Cellular Roles and Expression Landscape The expression profile of [SIX4](/details-gene/51804) points towards a highly specialized function in epithelial tissues, particularly those characterized by the presence of cilia. **Overall**, the gene shows its highest significance in [multi-ciliated epithelial cell](/details-cell/CL0005012) (CSI: 3.30) and [ciliated epithelial cell](/details-cell/CL0000067) (CSI: 3.19). This pattern is further reinforced by its high significance in more specific subtypes, including [lung ciliated cell](/details-cell/CL1000271) (CSI: 2.51) and [ciliated columnar cell of tracheobronchial tree](/details-cell/CL0002145) (CSI: 1.38). This consistent enrichment suggests that [SIX4](/details-gene/51804) is not merely expressed in these cells but may serve as a defining transcriptional regulator essential for their identity and function. Its notable expression in [basal cell](/details-cell/CL0000646) (CSI: 2.19), which are progenitor cells in many epithelial tissues, may indicate a role in the differentiation pathway leading to the ciliated cell fate. While its developmental roles are broad, the available expression data in adult tissues strongly anchors its primary function to the biology of ciliated epithelia. ## Pathways and Molecular Function [SIX4](/details-gene/51804) functions as a sequence-specific DNA-binding transcription factor, localizing to the [nucleus](/details-cell/GO:0005634) and [chromatin](/details-cell/GO:0000785) where it participates in [transcription regulator complex](/details-cell/GO:0005667)es. Its primary molecular activities involve [rna polymerase ii cis-regulatory region sequence-specific dna binding](/details-cell/GO:0000978) and subsequent regulation of gene expression. The gene is associated with a diverse range of biological processes, underscoring its importance as a developmental regulator. Key annotated functions include: * **Morphogenesis and Development:** [SIX4](/details-gene/51804) is integral to [anatomical structure morphogenesis](/details-cell/GO:0009653), with specific roles in the development of the [inner ear](/details-cell/GO:0042472), [male gonad](/details-cell/GO:0008584), [thymus](/details-cell/GO:0048538), and [skeletal muscle tissue](/details-cell/GO:0007519). A study by O'Neill et al. identified SIX4 as a binding factor in the muscle creatine kinase enhancer, corroborating its role in muscle development ([Link](https://doi.org/10.1128/mcb.24.5.2132-2143.2004)). * **Transcriptional Regulation:** It can function as both a transcriptional activator ([positive regulation of dna-templated transcription](/details-cell/GO:0045893)) and a repressor ([negative regulation of dna-templated transcription](/details-cell/GO:0045892)), suggesting a context-dependent regulatory mechanism. * **Cell Fate and Survival:** The gene is involved in the [generation of neurons](/details-cell/GO:0048699) and simultaneously participates in the [negative regulation of apoptotic process](/details-cell/GO:0043066), which may be crucial for the survival of specific cell types during and after development. This anti-apoptotic function, combined with its high expression in ciliated cells, suggests a potential role in maintaining the integrity of epithelial barriers. ## Research Directions The robust and specific expression of [SIX4](/details-gene/51804) in ciliated epithelial cells, juxtaposed with its broad developmental functions, provides fertile ground for further investigation. Its role appears to transition from a widespread developmental morphogen to a specialized regulator of terminally differentiated cells in adult tissues. Based on the available data, several testable hypotheses can be proposed: 1. **[SIX4](/details-gene/51804) is a master regulator of ciliogenesis in airway epithelial progenitor cells.** Its expression in [basal cell](/details-cell/CL0000646)s and high significance in multiple mature ciliated cell types suggests it may drive the transcriptional program required for ciliated cell differentiation. 2. **[SIX4](/details-gene/51804) is essential for the long-term survival and maintenance of ciliated cells.** Given its annotated role in the [negative regulation of apoptotic process](/details-cell/GO:0043066), [SIX4](/details-gene/51804) may protect these cells, which are constantly exposed to environmental insults, from premature cell death. To directly test the first hypothesis, a key experiment would be to use an *in vitro* air-liquid interface (ALI) culture system with primary human bronchial epithelial cells. **Knockdown of [SIX4](/details-gene/51804) using shRNA or CRISPR interference prior to inducing differentiation could be performed.** The impact on ciliated cell formation would be assessed via immunofluorescence staining for ciliary markers (e.g., acetylated α-tubulin, FOXJ1) and quantified. Concurrently, RNA sequencing at different time points during differentiation would reveal the downstream transcriptional networks controlled by [SIX4](/details-gene/51804) and identify direct targets involved in the specification of the ciliated cell lineage. Given that dysfunctional ciliated cells are implicated in chronic respiratory diseases such as COPD and asthma, [SIX4](/details-gene/51804) presents a potential therapeutic target. As a transcription factor, it is challenging to target directly. However, strategies aimed at modulating its activity could be explored. If it is indeed a pro-differentiation factor, therapeutic approaches could focus on the **activation** of [SIX4](/details-gene/51804) or its downstream pathways using small molecules to promote epithelial repair and restore mucociliary clearance in damaged airways.

Genular Protein ID: 1350987809

Symbol: SIX4_HUMAN

Name: Homeobox protein SIX4

UniProtKB Accession Codes:

Q9UIU6 Q4QQH5 Q4V764

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 7 Ensembl 1 ExpressionAtlas 1 GO 40 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 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 SIGNOR 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: 10640827

Title: Structure and chromosome mapping of the human SIX4 and murine Six4 genes.

PubMed ID: 10640827

DOI: 10.1159/000015407

PubMed ID: 12508121

Title: The DNA sequence and analysis of human chromosome 14.

PubMed ID: 12508121

DOI: 10.1038/nature01348

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: 14966291

Title: Quantitative proteomic identification of six4 as the trex-binding factor in the muscle creatine kinase enhancer.

PubMed ID: 14966291

DOI: 10.1128/mcb.24.5.2132-2143.2004

PubMed ID: 17525332

Title: ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.

PubMed ID: 17525332

DOI: 10.1126/science.1140321

PubMed ID: 21406692

Title: System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation.

PubMed ID: 21406692

DOI: 10.1126/scisignal.2001570

PubMed ID: 16959974

Title: The consensus coding sequences of human breast and colorectal cancers.

PubMed ID: 16959974

DOI: 10.1126/science.1133427

Sequence Information:

  • Length: 781
  • Mass: 82933
  • Checksum: 0054080AFF7BFF7E
  • Sequence:
    • MSSSSPTGQI ASAADIKQEN GMESASEGQE AHREVAGGAA VGLSPPAPAP FPLEPGDAAT 
AAARVSGEEG AVAAAAAGAA ADQVQLHSEL LGRHHHAAAA AAQTPLAFSP DHVACVCEAL 
QQGGNLDRLA RFLWSLPQSD LLRGNESLLK ARALVAFHQG IYPELYSILE SHSFESANHP 
LLQQLWYKAR YTEAERARGR PLGAVDKYRL RRKFPLPRTI WDGEETVYCF KEKSRNALKE 
LYKQNRYPSP AEKRHLAKIT GLSLTQVSNW FKNRRQRDRN PSETQSKSES DGNPSTEDES 
SKGHEDLSPH PLSSSSDGIT NLSLSSHMEP VYMQQIGNAK ISLSSSGVLL NGSLVPASTS 
PVFLNGNSFI QGPSGVILNG LNVGNTQAVA LNPPKMSSNI VSNGISMTDI LGSTSQDVKE 
FKVLQSSANS ATTTSYSPSV PVSFPGLIPS TEVKREGIQT VASQDGGSVV TFTTPVQINQ 
YGIVQIPNSG ANSQFLNGSI GFSPLQLPPV SVAASQGNIS VSSSTSDGST FTSESTTVQQ 
GKVFLSSLAP SAVVYTVPNT GQTIGSVKQE GLERSLVFSQ LMPVNQNAQV NANLSSENIS 
GSGLHPLASS LVNVSPTHNF SLSPSTLLNP TELNRDIADS QPMSAPVASK STVTSVSNTN 
YATLQNCSLI TGQDLLSVPM TQAALGEIVP TAEDQVGHPS PAVHQDFVQE HRLVLQSVAN 
MKENFLSNSE SKATSSLMML DSKSKYVLDG MVDTVCEDLE TDKKELAKLQ TVQLDEDMQD 
L