HGNC Family | Homeoboxes |
Name | SIX homeobox 3 |
Description | This gene encodes a member of the sine oculis homeobox transcription factor family. The encoded protein plays a role in eye development. Mutations in this gene have been associated with holoprosencephaly type 2. [provided by RefSeq, Oct 2009] |
Summary |
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In genetically heterogeneous cases, both loss‐of‐function mutations and inherited deletions of SIX3 cause variable phenotypes with incomplete penetrance, highlighting its dosage‐dependent role in early neural and ocular development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in congenital malformations, SIX3 modulates neural progenitor cell behavior. In the developing telencephalon, ectopic expression of SIX3 accelerates cell cycle exit and enhances clonal expansion, thereby maintaining neural precursors in an undifferentiated state. In the retina, SIX3 interacts with chromatin modifiers such as MTA1 to regulate the transcription of key genes (for example, rhodopsin), underscoring its function in fine‐tuning the gene networks that control neural and sensory cell fate decisions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSIX3 is also increasingly recognized for its context‐dependent roles in human cancers. In some tumors—such as glioma and astrocytoma—epigenetic silencing of SIX3 via promoter hypermethylation is associated with enhanced cell cycle progression, invasion, and tumorigenesis, suggesting a tumor‐suppressive function. In contrast, in lung adenocarcinoma, esophageal cancer, and head and neck carcinomas, SIX3 can be overexpressed or deregulated through mechanisms that involve post‐translational degradation (for example, via the E3 ubiquitin ligase TRIM27) or modulation by microRNAs (e.g. miR-4306). In these settings, SIX3 influences key signaling pathways such as Wnt/β‐catenin and PI3K/Akt, and its interactions with cofactors like NOR-1 further modulate transcriptional outputs that control proliferation, migration, and metastasis. 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Synonyms | HPE2 |
Proteins | SIX3_HUMAN |
NCBI Gene ID | 6496 |
API | |
Download Associations | |
Predicted Functions |
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Co-expressed Genes |
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Expression in Tissues and Cell Lines |
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SIX3 has 4,977 functional associations with biological entities spanning 8 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 101 datasets.
Click the + buttons to view associations for SIX3 from the datasets below.
If available, associations are ranked by standardized value
Dataset | Summary | |
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Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles | tissues with high or low expression of SIX3 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset. | |
Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles | tissues with high or low expression of SIX3 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset. | |
Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray | tissue samples with high or low expression of SIX3 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset. | |
Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles | tissues with high or low expression of SIX3 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset. | |
BioGPS Cell Line Gene Expression Profiles | cell lines with high or low expression of SIX3 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset. | |
BioGPS Human Cell Type and Tissue Gene Expression Profiles | cell types and tissues with high or low expression of SIX3 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset. | |
BioGPS Mouse Cell Type and Tissue Gene Expression Profiles | cell types and tissues with high or low expression of SIX3 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset. | |
CCLE Cell Line Gene CNV Profiles | cell lines with high or low copy number of SIX3 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset. | |
CCLE Cell Line Gene Expression Profiles | cell lines with high or low expression of SIX3 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset. | |
CellMarker Gene-Cell Type Associations | cell types associated with SIX3 gene from the CellMarker Gene-Cell Type Associations dataset. | |
ChEA Transcription Factor Binding Site Profiles | transcription factor binding site profiles with transcription factor binding evidence at the promoter of SIX3 gene from the CHEA Transcription Factor Binding Site Profiles dataset. | |
ChEA Transcription Factor Targets | transcription factors binding the promoter of SIX3 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset. | |
ChEA Transcription Factor Targets 2022 | transcription factors binding the promoter of SIX3 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset. | |
CMAP Signatures of Differentially Expressed Genes for Small Molecules | small molecule perturbations changing expression of SIX3 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset. | |
COMPARTMENTS Curated Protein Localization Evidence Scores | cellular components containing SIX3 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset. | |
COMPARTMENTS Curated Protein Localization Evidence Scores 2025 | cellular components containing SIX3 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset. | |
COMPARTMENTS Text-mining Protein Localization Evidence Scores | cellular components co-occuring with SIX3 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset. | |
COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 | cellular components co-occuring with SIX3 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset. | |
COSMIC Cell Line Gene CNV Profiles | cell lines with high or low copy number of SIX3 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset. | |
COSMIC Cell Line Gene Mutation Profiles | cell lines with SIX3 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset. | |
CTD Gene-Chemical Interactions | chemicals interacting with SIX3 gene/protein from the curated CTD Gene-Chemical Interactions dataset. | |
CTD Gene-Disease Associations | diseases associated with SIX3 gene/protein from the curated CTD Gene-Disease Associations dataset. | |
dbGAP Gene-Trait Associations | traits associated with SIX3 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset. | |
DepMap CRISPR Gene Dependency | cell lines with fitness changed by SIX3 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset. | |
DISEASES Curated Gene-Disease Association Evidence Scores | diseases involving SIX3 gene from the DISEASES Curated Gene-Disease Assocation Evidence Scores dataset. | |
DISEASES Curated Gene-Disease Association Evidence Scores 2025 | diseases involving SIX3 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset. | |
DISEASES Experimental Gene-Disease Association Evidence Scores | diseases associated with SIX3 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset. | |
DISEASES Experimental Gene-Disease Association Evidence Scores 2025 | diseases associated with SIX3 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset. | |
DISEASES Text-mining Gene-Disease Association Evidence Scores | diseases co-occuring with SIX3 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset. | |
DISEASES Text-mining Gene-Disease Association Evidence Scores 2025 | diseases co-occuring with SIX3 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset. | |
DisGeNET Gene-Disease Associations | diseases associated with SIX3 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset. | |
DisGeNET Gene-Phenotype Associations | phenotypes associated with SIX3 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset. | |
ENCODE Histone Modification Site Profiles | histone modification site profiles with high histone modification abundance at SIX3 gene from the ENCODE Histone Modification Site Profiles dataset. | |
ENCODE Transcription Factor Binding Site Profiles | transcription factor binding site profiles with transcription factor binding evidence at the promoter of SIX3 gene from the ENCODE Transcription Factor Binding Site Profiles dataset. | |
ENCODE Transcription Factor Targets | transcription factors binding the promoter of SIX3 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset. | |
ESCAPE Omics Signatures of Genes and Proteins for Stem Cells | PubMedIDs of publications reporting gene signatures containing SIX3 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset. | |
GAD Gene-Disease Associations | diseases associated with SIX3 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset. | |
GAD High Level Gene-Disease Associations | diseases associated with SIX3 gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset. | |
GDSC Cell Line Gene Expression Profiles | cell lines with high or low expression of SIX3 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset. | |
GeneRIF Biological Term Annotations | biological terms co-occuring with SIX3 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset. | |
GeneSigDB Published Gene Signatures | PubMedIDs of publications reporting gene signatures containing SIX3 from the GeneSigDB Published Gene Signatures dataset. | |
GEO Signatures of Differentially Expressed Genes for Diseases | disease perturbations changing expression of SIX3 gene from the GEO Signatures of Differentially Expressed Genes for Diseases dataset. | |
GEO Signatures of Differentially Expressed Genes for Gene Perturbations | gene perturbations changing expression of SIX3 gene from the GEO Signatures of Differentially Expressed Genes for Gene Perturbations dataset. | |
GEO Signatures of Differentially Expressed Genes for Kinase Perturbations | kinase perturbations changing expression of SIX3 gene from the GEO Signatures of Differentially Expressed Genes for Kinase Perturbations dataset. | |
GEO Signatures of Differentially Expressed Genes for Small Molecules | small molecule perturbations changing expression of SIX3 gene from the GEO Signatures of Differentially Expressed Genes for Small Molecules dataset. | |
GEO Signatures of Differentially Expressed Genes for Transcription Factor Perturbations | transcription factor perturbations changing expression of SIX3 gene from the GEO Signatures of Differentially Expressed Genes for Transcription Factor Perturbations dataset. | |
GEO Signatures of Differentially Expressed Genes for Viral Infections | virus perturbations changing expression of SIX3 gene from the GEO Signatures of Differentially Expressed Genes for Viral Infections dataset. | |
GO Biological Process Annotations 2015 | biological processes involving SIX3 gene from the curated GO Biological Process Annotations 2015 dataset. | |
GO Biological Process Annotations 2023 | biological processes involving SIX3 gene from the curated GO Biological Process Annotations 2023 dataset. | |
GO Biological Process Annotations 2025 | biological processes involving SIX3 gene from the curated GO Biological Process Annotations2025 dataset. | |
GO Cellular Component Annotations 2015 | cellular components containing SIX3 protein from the curated GO Cellular Component Annotations 2015 dataset. | |
GO Cellular Component Annotations 2023 | cellular components containing SIX3 protein from the curated GO Cellular Component Annotations 2023 dataset. | |
GO Cellular Component Annotations 2025 | cellular components containing SIX3 protein from the curated GO Cellular Component Annotations 2025 dataset. | |
GO Molecular Function Annotations 2015 | molecular functions performed by SIX3 gene from the curated GO Molecular Function Annotations 2015 dataset. | |
GO Molecular Function Annotations 2023 | molecular functions performed by SIX3 gene from the curated GO Molecular Function Annotations 2023 dataset. | |
GO Molecular Function Annotations 2025 | molecular functions performed by SIX3 gene from the curated GO Molecular Function Annotations 2025 dataset. | |
GTEx Tissue Gene Expression Profiles | tissues with high or low expression of SIX3 gene relative to other tissues from the GTEx Tissue Gene Expression Profiles dataset. | |
GTEx Tissue Gene Expression Profiles 2023 | tissues with high or low expression of SIX3 gene relative to other tissues from the GTEx Tissue Gene Expression Profiles 2023 dataset. | |
GTEx Tissue Sample Gene Expression Profiles | tissue samples with high or low expression of SIX3 gene relative to other tissue samples from the GTEx Tissue Sample Gene Expression Profiles dataset. | |
Heiser et al., PNAS, 2011 Cell Line Gene Expression Profiles | cell lines with high or low expression of SIX3 gene relative to other cell lines from the Heiser et al., PNAS, 2011 Cell Line Gene Expression Profiles dataset. | |
HPA Cell Line Gene Expression Profiles | cell lines with high or low expression of SIX3 gene relative to other cell lines from the HPA Cell Line Gene Expression Profiles dataset. | |
HPA Tissue Gene Expression Profiles | tissues with high or low expression of SIX3 gene relative to other tissues from the HPA Tissue Gene Expression Profiles dataset. | |
HPO Gene-Disease Associations | phenotypes associated with SIX3 gene by mapping known disease genes to disease phenotypes from the HPO Gene-Disease Associations dataset. | |
HuBMAP ASCT+B Annotations | cell types associated with SIX3 gene from the HuBMAP ASCT+B dataset. | |
HuBMAP ASCT+B Augmented with RNA-seq Coexpression | cell types associated with SIX3 gene from the HuBMAP ASCT+B Augmented with RNA-seq Coexpression dataset. | |
HuBMAP Azimuth Cell Type Annotations | cell types associated with SIX3 gene from the HuBMAP Azimuth Cell Type Annotations dataset. | |
HuGE Navigator Gene-Phenotype Associations | phenotypes associated with SIX3 gene by text-mining GWAS publications from the HuGE Navigator Gene-Phenotype Associations dataset. | |
InterPro Predicted Protein Domain Annotations | protein domains predicted for SIX3 protein from the InterPro Predicted Protein Domain Annotations dataset. | |
Klijn et al., Nat. Biotechnol., 2015 Cell Line Gene CNV Profiles | cell lines with high or low copy number of SIX3 gene relative to other cell lines from the Klijn et al., Nat. Biotechnol., 2015 Cell Line Gene CNV Profiles dataset. | |
Klijn et al., Nat. Biotechnol., 2015 Cell Line Gene Mutation Profiles | cell lines with SIX3 gene mutations from the Klijn et al., Nat. Biotechnol., 2015 Cell Line Gene Mutation Profiles dataset. | |
KnockTF Gene Expression Profiles with Transcription Factor Perturbations | transcription factor perturbations changing expression of SIX3 gene from the KnockTF Gene Expression Profiles with Transcription Factor Perturbations dataset. | |
LINCS L1000 CMAP Chemical Perturbation Consensus Signatures | small molecule perturbations changing expression of SIX3 gene from the LINCS L1000 CMAP Chemical Perturbations Consensus Signatures dataset. | |
LINCS L1000 CMAP CRISPR Knockout Consensus Signatures | gene perturbations changing expression of SIX3 gene from the LINCS L1000 CMAP CRISPR Knockout Consensus Signatures dataset. | |
LOCATE Curated Protein Localization Annotations | cellular components containing SIX3 protein in low- or high-throughput protein localization assays from the LOCATE Curated Protein Localization Annotations dataset. | |
LOCATE Predicted Protein Localization Annotations | cellular components predicted to contain SIX3 protein from the LOCATE Predicted Protein Localization Annotations dataset. | |
MGI Mouse Phenotype Associations 2023 | phenotypes of transgenic mice caused by SIX3 gene mutations from the MGI Mouse Phenotype Associations 2023 dataset. | |
MotifMap Predicted Transcription Factor Targets | transcription factors regulating expression of SIX3 gene predicted using known transcription factor binding site motifs from the MotifMap Predicted Transcription Factor Targets dataset. | |
MPO Gene-Phenotype Associations | phenotypes of transgenic mice caused by SIX3 gene mutations from the MPO Gene-Phenotype Associations dataset. | |
MSigDB Cancer Gene Co-expression Modules | co-expressed genes for SIX3 from the MSigDB Cancer Gene Co-expression Modules dataset. | |
MSigDB Signatures of Differentially Expressed Genes for Cancer Gene Perturbations | gene perturbations changing expression of SIX3 gene from the MSigDB Signatures of Differentially Expressed Genes for Cancer Gene Perturbations dataset. | |
OMIM Gene-Disease Associations | phenotypes associated with SIX3 gene from the curated OMIM Gene-Disease Associations dataset. | |
Pathway Commons Protein-Protein Interactions | interacting proteins for SIX3 from the Pathway Commons Protein-Protein Interactions dataset. | |
PerturbAtlas Signatures of Differentially Expressed Genes for Gene Perturbations | gene perturbations changing expression of SIX3 gene from the PerturbAtlas Signatures of Differentially Expressed Genes for Gene Perturbations dataset. | |
PerturbAtlas Signatures of Differentially Expressed Genes for Mouse Gene Perturbations | gene perturbations changing expression of SIX3 gene from the PerturbAtlas Signatures of Differentially Expressed Genes for Gene Perturbations dataset. | |
PFOCR Pathway Figure Associations 2023 | pathways involving SIX3 protein from the PFOCR Pathway Figure Associations 2023 dataset. | |
PFOCR Pathway Figure Associations 2024 | pathways involving SIX3 protein from the Wikipathways PFOCR 2024 dataset. | |
Replogle et al., Cell, 2022 RPE1 Essential Perturb-seq Gene Perturbation Signatures | gene perturbations changing expression of SIX3 gene from the Replogle et al., Cell, 2022 RPE1 Essential Perturb-seq Gene Perturbation Signatures dataset. | |
Roadmap Epigenomics Cell and Tissue DNA Methylation Profiles | cell types and tissues with high or low DNA methylation of SIX3 gene relative to other cell types and tissues from the Roadmap Epigenomics Cell and Tissue DNA Methylation Profiles dataset. | |
Roadmap Epigenomics Histone Modification Site Profiles | histone modification site profiles with high histone modification abundance at SIX3 gene from the Roadmap Epigenomics Histone Modification Site Profiles dataset. | |
RummaGEO Drug Perturbation Signatures | drug perturbations changing expression of SIX3 gene from the RummaGEO Drug Perturbation Signatures dataset. | |
RummaGEO Gene Perturbation Signatures | gene perturbations changing expression of SIX3 gene from the RummaGEO Gene Perturbation Signatures dataset. | |
Tabula Sapiens Gene-Cell Associations | cell types with high or low expression of SIX3 gene relative to other cell types from the Tabula Sapiens Gene-Cell Associations dataset. | |
TargetScan Predicted Conserved microRNA Targets | microRNAs regulating expression of SIX3 gene predicted using conserved miRNA seed sequences from the TargetScan Predicted Conserved microRNA Targets dataset. | |
TargetScan Predicted Nonconserved microRNA Targets | microRNAs regulating expression of SIX3 gene predicted using nonconserved miRNA seed sequences from the TargetScan Predicted Nonconserved microRNA Targets dataset. | |
TCGA Signatures of Differentially Expressed Genes for Tumors | tissue samples with high or low expression of SIX3 gene relative to other tissue samples from the TCGA Signatures of Differentially Expressed Genes for Tumors dataset. | |
TISSUES Curated Tissue Protein Expression Evidence Scores | tissues with high expression of SIX3 protein from the TISSUES Curated Tissue Protein Expression Evidence Scores dataset. | |
TISSUES Curated Tissue Protein Expression Evidence Scores 2025 | tissues with high expression of SIX3 protein from the TISSUES Curated Tissue Protein Expression Evidence Scores 2025 dataset. | |
TISSUES Experimental Tissue Protein Expression Evidence Scores | tissues with high expression of SIX3 protein in proteomics datasets from the TISSUES Experimental Tissue Protein Expression Evidence Scores dataset. | |
TISSUES Text-mining Tissue Protein Expression Evidence Scores | tissues co-occuring with SIX3 protein in abstracts of biomedical publications from the TISSUES Text-mining Tissue Protein Expression Evidence Scores dataset. | |
TISSUES Text-mining Tissue Protein Expression Evidence Scores 2025 | tissues co-occuring with SIX3 protein in abstracts of biomedical publications from the TISSUES Text-mining Tissue Protein Expression Evidence Scores 2025 dataset. | |
WikiPathways Pathways 2024 | pathways involving SIX3 protein from the WikiPathways Pathways 2024 dataset. | |