ID4 (Inhibitor of DNA Binding 4, HLH Protein)
A key regulator of cell differentiation and tumor suppression, frequently silenced in cancer.
Gene Information Card
| Symbol | ID4 |
|---|---|
| Full Name | Inhibitor of DNA Binding 4, HLH Protein |
| Gene Type | Protein coding |
| Chromosomal Location | 6p22.3 |
| NCBI Gene ID | 3400 ncbi.nlm.nih.gov/gene/3400 |
| Ensembl ID | ENSG00000172201 |
| UniProt ID | P47928 |
| OMIM ID | 600581 |
| HGNC ID | 5363 |
| Aliases | bHLHb27, ID4_HUMAN |
Description
ID4 encodes a member of the inhibitor of DNA binding (ID) family of helix-loop-helix (HLH) proteins. ID4 lacks a basic DNA-binding domain and functions as a dominant-negative regulator of basic HLH transcription factors. It plays critical roles in cell growth, differentiation, and senescence. ID4 is frequently silenced by promoter hypermethylation in various cancers, suggesting a tumor suppressor role. It is also involved in neural and B-cell development.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Breast Cancer | ID4 promoter hypermethylation leads to loss of expression, contributing to tumor progression and poor prognosis. | PMID: 15696293; PMID: 21573163 |
| Gastric Cancer | ID4 silencing via DNA methylation is associated with advanced tumor stage and lymph node metastasis. | PMID: 19189131 |
| Acute Lymphoblastic Leukemia (ALL) | ID4 is a target of chromosomal translocation t(6;14)(p22;q32) in B-cell ALL, leading to ID4 overexpression and impaired B-cell differentiation. | PMID: 12663455 |
| Colorectal Cancer | Reduced ID4 expression correlates with microsatellite instability and CpG island methylator phenotype (CIMP). | PMID: 19189131 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 5.2 | Low |
| Breast | 3.8 | Low |
| Stomach | 2.1 | Low |
| Lymph node | 1.5 | Not detected |
| Testis | 0.9 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| MCF7 (breast cancer) | 0.6 | Low expression; often methylated |
| K562 (leukemia) | 1.2 | Low expression |
| HeLa (cervical cancer) | 0.3 | Not detected |
| HCT116 (colorectal cancer) | 0.4 | Not detected |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1A>G (p.Met1?) | Missense | <0.1% | Likely loss of start codon; predicted loss of function |
| c.172C>T (p.Arg58Trp) | Missense | <0.1% | Unknown significance; rare in population databases |
| ID4 promoter hypermethylation | Epigenetic | Common in breast, gastric, colorectal cancers | Transcriptional silencing; loss of tumor suppressor function |
Mutation functional classification
Loss of Function (LOF)
Promoter hypermethylation and rare missense variants (e.g., p.Met1?) lead to reduced or absent ID4 protein, impairing its ability to inhibit bHLH transcription factors and promote differentiation.
Gain of Function (GOF)
Not well documented; ID4 overexpression in B-ALL due to translocation may represent a gain-of-function mechanism, but functional evidence is limited.
Dominant Negative (DN)
ID4 naturally acts as a dominant-negative regulator of bHLH factors by forming heterodimers that cannot bind DNA. Mutations that stabilize this interaction could enhance dominant-negative activity.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Regulation of bHLH transcription factors (Reactome: R-HSA-9616222)
• Transcriptional regulation by RUNX1 (Reactome: R-HSA-8878171)
• Cellular senescence (KEGG: hsa04218)
Protein Summary
ID4 is a 161-amino acid protein (17.5 kDa) belonging to the ID family. It contains a helix-loop-helix (HLH) domain but lacks a basic DNA-binding region. ID4 forms heterodimers with bHLH transcription factors (e.g., E12/E47, MyoD, NeuroD), preventing them from binding DNA and thereby inhibiting transcription of genes involved in differentiation. ID4 is predominantly nuclear and is expressed at low levels in most adult tissues, with highest expression in brain and breast. Loss of ID4 expression via promoter methylation is a common event in several cancers, supporting its role as a tumor suppressor.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| ID4 Knockout HEK293 Cell Line | EDJ-KQ50377 | Human | 3400 | Details Get a Quote |
| ID4 Knockout HeLa Cell Line | EDJ-KQ53605 | Human | 3400 | Details Get a Quote |
| ID4 Knockout A-549 Cell Line | EDJ-KQ62074 | Human | 3400 | Details Get a Quote |
| ID4 Knockout HCT 116 Cell Line | EDJ-KQ70556 | Human | 3400 | Details Get a Quote |
