HES4 Gene

HGNC Family Basic helix-loop-helix proteins (BHLH)
Name hes family bHLH transcription factor 4
Description Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in anterior/posterior pattern specification and regulation of transcription by RNA polymerase II. Predicted to be located in chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Mar 2025]
Summary
{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HES4 is a Notch‐induced transcriptional repressor whose functions appear to be highly context‐dependent. In neuronal cells, for example, epigenetic dysregulation of the HES4 promoter—marked by loss of H3K4me3 and increased DNA methylation—is associated with altered expression of HES4 and its downstream targets (such as MASH1 and P21), which in turn correlates with neuronal degeneration in Huntington’s disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the hematopoietic system, HES4 is robustly upregulated via Notch signaling during early T‐cell development. Unlike its paralog HES1, HES4 not only suppresses alternative fate programs (inhibiting natural killer and myeloid lineages) but also uniquely promotes the initiation of early T‐cell differentiation—although its ectopic expression is not solely sufficient to enforce a full T‐cell lineage commitment. Importantly, knockdown studies indicate that reducing HES4 levels impairs normal T‐cell development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In a distinct disease context, high HES4 expression in osteosarcoma correlates with a more aggressive tumor phenotype, as it acts to prevent osteoblastic differentiation, thereby contributing to poorer metastasis‐free and overall survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Collectively, these studies suggest that HES4 is an important mediator of Notch-dependent cell fate decisions – modulating neurodevelopment, T-cell lineage specification, and osteogenic differentiation – with its dysregulation contributing to neurodegenerative conditions and tumor aggressiveness.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Guang Bai, Iris Cheung, Hennady P Shulha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddu561"}], "href": "https://doi.org/10.1093/hmg/ddu561"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25480889"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25480889"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Matthias De Decker, Marieke Lavaert, Juliette Roels, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Haematologica (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3324/haematol.2019.226126"}], "href": "https://doi.org/10.3324/haematol.2019.226126"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31919081"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31919081"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Madonna McManus, Eugenie Kleinerman, Yanwen Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hes4: A potential prognostic biomarker for newly diagnosed patients with high-grade osteosarcoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pediatr Blood Cancer (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/pbc.26318"}], "href": "https://doi.org/10.1002/pbc.26318"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27786411"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27786411"}]}]}]}
Synonyms BHLHB42
Proteins HES4_HUMAN
NCBI Gene ID 57801
API
Download Associations
Predicted Functions View HES4's ARCHS4 Predicted Functions.
Co-expressed Genes View HES4's ARCHS4 Predicted Functions.
Expression in Tissues and Cell Lines View HES4's ARCHS4 Predicted Functions.

Functional Associations

HES4 has 3,986 functional associations with biological entities spanning 8 categories (molecular profile, organism, functional term, phrase or reference, chemical, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 94 datasets.

Click the + buttons to view associations for HES4 from the datasets below.

If available, associations are ranked by standardized value

Dataset Summary
Achilles Cell Line Gene Essentiality Profiles cell lines with fitness changed by HES4 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles tissues with high or low expression of HES4 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles tissue samples with high or low expression of HES4 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray tissue samples with high or low expression of HES4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq tissue samples with high or low expression of HES4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles tissues with high or low expression of HES4 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
BioGPS Human Cell Type and Tissue Gene Expression Profiles cell types and tissues with high or low expression of HES4 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
CCLE Cell Line Gene CNV Profiles cell lines with high or low copy number of HES4 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 HES4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
CellMarker Gene-Cell Type Associations cell types associated with HES4 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 HES4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
ChEA Transcription Factor Targets transcription factors binding the promoter of HES4 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 HES4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
COMPARTMENTS Curated Protein Localization Evidence Scores cellular components containing HES4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
COMPARTMENTS Curated Protein Localization Evidence Scores 2025 cellular components containing HES4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
COMPARTMENTS Text-mining Protein Localization Evidence Scores cellular components co-occuring with HES4 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 HES4 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 HES4 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
COSMIC Cell Line Gene Mutation Profiles cell lines with HES4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
CTD Gene-Chemical Interactions chemicals interacting with HES4 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
CTD Gene-Disease Associations diseases associated with HES4 gene/protein from the curated CTD Gene-Disease Associations dataset.
DepMap CRISPR Gene Dependency cell lines with fitness changed by HES4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
DISEASES Experimental Gene-Disease Association Evidence Scores 2025 diseases associated with HES4 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 HES4 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 HES4 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 HES4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
DisGeNET Gene-Phenotype Associations phenotypes associated with HES4 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 HES4 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 HES4 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
ENCODE Transcription Factor Targets transcription factors binding the promoter of HES4 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 HES4 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
GeneSigDB Published Gene Signatures PubMedIDs of publications reporting gene signatures containing HES4 from the GeneSigDB Published Gene Signatures dataset.
GEO Signatures of Differentially Expressed Genes for Diseases disease perturbations changing expression of HES4 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 HES4 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 HES4 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 HES4 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 HES4 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 HES4 gene from the GEO Signatures of Differentially Expressed Genes for Viral Infections dataset.
GO Biological Process Annotations 2015 biological processes involving HES4 gene from the curated GO Biological Process Annotations 2015 dataset.
GO Biological Process Annotations 2023 biological processes involving HES4 gene from the curated GO Biological Process Annotations 2023 dataset.
GO Biological Process Annotations 2025 biological processes involving HES4 gene from the curated GO Biological Process Annotations2025 dataset.
GO Cellular Component Annotations 2015 cellular components containing HES4 protein from the curated GO Cellular Component Annotations 2015 dataset.
GO Cellular Component Annotations 2023 cellular components containing HES4 protein from the curated GO Cellular Component Annotations 2023 dataset.
GO Cellular Component Annotations 2025 cellular components containing HES4 protein from the curated GO Cellular Component Annotations 2025 dataset.
GO Molecular Function Annotations 2015 molecular functions performed by HES4 gene from the curated GO Molecular Function Annotations 2015 dataset.
GO Molecular Function Annotations 2023 molecular functions performed by HES4 gene from the curated GO Molecular Function Annotations 2023 dataset.
GO Molecular Function Annotations 2025 molecular functions performed by HES4 gene from the curated GO Molecular Function Annotations 2025 dataset.
GTEx Tissue Gene Expression Profiles tissues with high or low expression of HES4 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 HES4 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 HES4 gene relative to other tissue samples from the GTEx Tissue Sample Gene Expression Profiles dataset.
GTEx Tissue-Specific Aging Signatures tissue samples with high or low expression of HES4 gene relative to other tissue samples from the GTEx Tissue-Specific Aging Signatures dataset.
GWAS Catalog SNP-Phenotype Associations 2025 phenotypes associated with HES4 gene in GWAS datasets from the GWAS Catalog SNP-Phenotype Associations 2025 dataset.
Heiser et al., PNAS, 2011 Cell Line Gene Expression Profiles cell lines with high or low expression of HES4 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 HES4 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 HES4 gene relative to other tissues from the HPA Tissue Gene Expression Profiles dataset.
HPA Tissue Sample Gene Expression Profiles tissue samples with high or low expression of HES4 gene relative to other tissue samples from the HPA Tissue Sample Gene Expression Profiles dataset.
Hub Proteins Protein-Protein Interactions interacting hub proteins for HES4 from the curated Hub Proteins Protein-Protein Interactions dataset.
HuBMAP ASCT+B Annotations cell types associated with HES4 gene from the HuBMAP ASCT+B dataset.
HuBMAP ASCT+B Augmented with RNA-seq Coexpression cell types associated with HES4 gene from the HuBMAP ASCT+B Augmented with RNA-seq Coexpression dataset.
HuBMAP Azimuth Cell Type Annotations cell types associated with HES4 gene from the HuBMAP Azimuth Cell Type Annotations dataset.
InterPro Predicted Protein Domain Annotations protein domains predicted for HES4 protein from the InterPro Predicted Protein Domain Annotations dataset.
JASPAR Predicted Human Transcription Factor Targets 2025 transcription factors regulating expression of HES4 gene predicted using known transcription factor binding site motifs from the JASPAR Predicted Human Transcription Factor Targets dataset.
JASPAR Predicted Transcription Factor Targets transcription factors regulating expression of HES4 gene predicted using known transcription factor binding site motifs from the JASPAR Predicted Transcription Factor Targets dataset.
KEGG Pathways 2026 pathways involving HES4 protein from the KEGG Pathways 2026 dataset.
Klijn et al., Nat. Biotechnol., 2015 Cell Line Gene CNV Profiles cell lines with high or low copy number of HES4 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 HES4 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 HES4 gene from the KnockTF Gene Expression Profiles with Transcription Factor Perturbations dataset.
LOCATE Curated Protein Localization Annotations cellular components containing HES4 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 HES4 protein from the LOCATE Predicted Protein Localization Annotations dataset.
MiRTarBase microRNA Targets microRNAs targeting HES4 gene in low- or high-throughput microRNA targeting studies from the MiRTarBase microRNA Targets dataset.
MotifMap Predicted Transcription Factor Targets transcription factors regulating expression of HES4 gene predicted using known transcription factor binding site motifs from the MotifMap Predicted Transcription Factor Targets dataset.
NIBR DRUG-seq U2OS MoA Box Gene Expression Profiles drug perturbations changing expression of HES4 gene from the NIBR DRUG-seq U2OS MoA Box dataset.
Pathway Commons Protein-Protein Interactions interacting proteins for HES4 from the Pathway Commons Protein-Protein Interactions dataset.
PerturbAtlas Signatures of Differentially Expressed Genes for Gene Perturbations gene perturbations changing expression of HES4 gene from the PerturbAtlas Signatures of Differentially Expressed Genes for Gene Perturbations dataset.
PFOCR Pathway Figure Associations 2023 pathways involving HES4 protein from the PFOCR Pathway Figure Associations 2023 dataset.
PFOCR Pathway Figure Associations 2024 pathways involving HES4 protein from the Wikipathways PFOCR 2024 dataset.
Replogle et al., Cell, 2022 K562 Essential Perturb-seq Gene Perturbation Signatures gene perturbations changing expression of HES4 gene from the Replogle et al., Cell, 2022 K562 Essential Perturb-seq Gene Perturbation Signatures dataset.
Replogle et al., Cell, 2022 K562 Genome-wide Perturb-seq Gene Perturbation Signatures gene perturbations changing expression of HES4 gene from the Replogle et al., Cell, 2022 K562 Genome-wide Perturb-seq Gene Perturbation Signatures dataset.
Replogle et al., Cell, 2022 RPE1 Essential Perturb-seq Gene Perturbation Signatures gene perturbations changing expression of HES4 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 HES4 gene relative to other cell types and tissues from the Roadmap Epigenomics Cell and Tissue DNA Methylation Profiles dataset.
Roadmap Epigenomics Cell and Tissue Gene Expression Profiles cell types and tissues with high or low expression of HES4 gene relative to other cell types and tissues from the Roadmap Epigenomics Cell and Tissue Gene Expression Profiles dataset.
Roadmap Epigenomics Histone Modification Site Profiles histone modification site profiles with high histone modification abundance at HES4 gene from the Roadmap Epigenomics Histone Modification Site Profiles dataset.
RummaGEO Drug Perturbation Signatures drug perturbations changing expression of HES4 gene from the RummaGEO Drug Perturbation Signatures dataset.
RummaGEO Gene Perturbation Signatures gene perturbations changing expression of HES4 gene from the RummaGEO Gene Perturbation Signatures dataset.
Tabula Sapiens Gene-Cell Associations cell types with high or low expression of HES4 gene relative to other cell types from the Tabula Sapiens Gene-Cell Associations dataset.
Tahoe Therapeutics Tahoe 100M Perturbation Atlas drug perturbations changing expression of HES4 gene from the Tahoe Therapeutics Tahoe 100M Perturbation Atlas dataset.
TargetScan Predicted Nonconserved microRNA Targets microRNAs regulating expression of HES4 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 HES4 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 HES4 protein from the TISSUES Curated Tissue Protein Expression Evidence Scores dataset.
TISSUES Curated Tissue Protein Expression Evidence Scores 2025 tissues with high expression of HES4 protein from the TISSUES Curated Tissue Protein Expression Evidence Scores 2025 dataset.
TISSUES Experimental Tissue Protein Expression Evidence Scores tissues with high expression of HES4 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 HES4 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 HES4 protein in abstracts of biomedical publications from the TISSUES Text-mining Tissue Protein Expression Evidence Scores 2025 dataset.
WikiPathways Pathways 2024 pathways involving HES4 protein from the WikiPathways Pathways 2024 dataset.