ID4 (inhibitor of DNA binding 4, dominant negative helix-loop-helix protein)

2008-04-01   Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France





The gene spans 3,3 kb on plus strand.


3 exons; mRNA 2,343 bp.



161 amino acids; 16.6 KDa; contains a poly-Ala (from amino acid 39 to 48), a helix-loop-helix motif (65 to 105), and a poly-Pro (118 to 124).


Expressed in various tissues.


ID4 is one of the members of the ID gene family : "Inhibitors of DNA binding". They are transcription factors which act as transcription inhibitory proteins. They are basic helix-loop-helix (bHLH) proteins which contain the bHLH dimerization domain, but lack the DNA binding domain. They are able to form heterodimers with other bHLH proteins, but inhibit the DNA binding, inactivating the process. Since bHLH proteins act as transcription factors, ID genes are transcription repressors, modulating various functions.
ID proteins play critical roles in early embryonic processes, growth, differentiation, senescence and apoptosis; they are also involved in angiogenesis.
ID4 is expressed in the central nervous system. ID4 is required for G1-S transition and enhance proliferation in early cortical progenitors. On the other hand, ID4 enhances RB1 -mediated inhibition of proliferation of differenciating neurons, either by direct interaction or through interaction with other molecules of the cell cycle machinery. Other ID genes are not redondant with ID4 during telencephalic development, supporting the idea that ID4 function is unique in this context (Yun et al, 2004). In immature neurons with high expression of ID proteins, heterodimers of bHLH-ID prevent DNA binding and expression of differentiation associated genes.
ID4 may play an important suppressive role in tumor progression, and its silencing by hypermethylation favours tumorogenesis (see below).

Implicated in

Entity name
B-cell acute lymphoblastic leukaemia (B-ALL) with t(6;14)(p22;q32) --> ID4 - IGH
ID4 was juxtaposed to the IGH enhancer, leading to ID4 overexpression. (Bellido et al 2003, Russell et al 2008).
Prognosis in this disease looks fair.
Entity name
Non Hodgkin lymphoma
ID4 promoter was found hypermethylated in follicular lymphomas, diffuse large B-cell lymphomas, as well as lymphoid cell lines (Hagiwara K et al 2007).
Entity name
Brain tumours
In oligodendroglial tumours and glioblastomas, ID4 is expressed in neoplastic astrocytes but not in neoplastic oligodendrocytes (Liang et al, 2005).
Entity name
Breast cancer
Hypermethylation of ID4 promoter and ID4 mRNA suppression was found in breast cancer cell lines as well as in primary breast cancers. In one study, it was a significant risk factor for nodal metastasis (Umetani et al, 2006). In another study, BRCA1, ER (estrogen receptor), and ID4 were found expressed in breast cancer specimens from patients with invasive carcinomas. Most of the patients who expressed BRCA1 also expressed ER, but were negative for ID4, and vice versa. BRCA1-ER and ID4 are linked in a negative correlation (Roldan et al 2006). Id4 regulates BRCA1 expression and may be involved in hormone-dependent regulation of BRCA1 homeostasis (de Candia et al 2004). ID4 is constitutively expressed in the normal human mammary epithelium but is suppressed in ER-.
Positive breast carcinomas and preneoplastic lesions. ER-negative carcinomas are Id4 positive (de Candia et al 2006).
These results support a possible role of Id4 as a tumor suppressor factor in the human breast and suggest that the expression of Id4 in the mammary ductal epithelium may be regulated by estrogen (de Candia et al 2006).
Entity name
Bladder cancer
ID4 is part of the 6p22.3 amplicon frequently observed in advanced stage bladder cancer. ID4, as well as E2F3 and DEK, was overexpressed in bladder cancer cell lines. This overexpression was correlated with the copy number. However, ID4 expression was equivalent in fresh cancer tissues and normal urothelium (Wu et al, 2005).
Entity name
Gastric cancer
ID4 promoter is hypermethylated and showed a low level of expression in 30% of gastric adenocarcinomas and in most gastric cancer cell lines, while its expression was high in normal gastric mucosa. Furthermore, there was a significant association of ID4 promoter hypermethylation / ID4 down regulation and that of hMLH1 and microsatellite instability (Chan et al 2003).
Entity name
Colorectal cancer
ID4 is silenced in colorectal cancer: Hypermethylation was found in half of the primary colorectal cancer specimens tested (and in cell lines as well), in 3/4 of liver metastases of colorectal cancer specimens tested, but not in normal epitheliums nor in adenomas. Moreover, the methylation status was correlated with the histopathological grade, and hypermethylation of ID4 was identified as a significant independant risk factor of poor prognosis (Umetani et al 2005).
Entity name
Rett syndrome
A significantly increased protein expression of ID genes was found in human brain tissue of Rett syndrome patients, compared to controls (Peddada et al 2006). Rett syndrome is a X-linked neurodevelopmental disorder resembling autism, and due to MECP2 (Xq28 ) mutations in most cases, more rarely due to mutations of CDKL5 (Xp22) or, much less convaincingly, NTNG1 (1p13).


Pubmed IDLast YearTitleAuthors
100663621999Id4 expression induces apoptosis in astrocytic cultures and is down-regulated by activation of the cAMP-dependent signal transduction pathway.Andres-Barquin PJ et al
158825802005Id4 is required for the correct timing of neural differentiation.Bedford L et al
111362502001Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach.Beger C et al
129698072003Id4 is deregulated by a t(6;14)(p22;q32) chromosomal translocation in a B-cell lineage acute lymphoblastic leukemia.Bellido M et al
145345432003Downregulation of ID4 by promoter hypermethylation in gastric adenocarcinoma.Chan AS et al
113167352001Hormonal regulation and differential actions of the helix-loop-helix transcriptional inhibitors of differentiation (Id1, Id2, Id3, and Id4) in Sertoli cells.Chaudhary J et al
175105332007Frequent DNA methylation but not mutation of the ID4 gene in malignant lymphoma.Hagiwara K et al
160188212005Id4 and FABP7 are preferentially expressed in cells with astrocytic features in oligodendrogliomas and oligoastrocytomas.Liang Y et al
106112212000Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms.Massari ME et al
166824352006Inhibitors of differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett syndrome.Peddada S et al
118403232001The regulation and function of the Id proteins in lymphocyte development.Rivera R et al
165825982006Tumoral expression of BRCA1, estrogen receptor alpha and ID4 protein in patients with sporadic breast cancer.Roldán G et al
179402042008t(6;14)(p22;q32): a new recurrent IGH@ translocation involving ID4 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).Russell LJ et al
146336212003Id4 regulates mammary epithelial cell growth and differentiation and is overexpressed in rat mammary gland carcinomas.Shan L et al
158979102005Aberrant hypermethylation of ID4 gene promoter region increases risk of lymph node metastasis in T1 breast cancer.Umetani N et al
155699772004Epigenetic inactivation of ID4 in colorectal carcinomas correlates with poor differentiation and unfavorable prognosis.Umetani N et al
158763502005Amplification and overexpression of the ID4 gene at 6p22.3 in bladder cancer.Wu Q et al
157230652005Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia.Yu L et al
154699682004Id4 regulates neural progenitor proliferation and differentiation in vivo.Yun K et al
168678662006Id4 messenger RNA and estrogen receptor expression: inverse correlation in human normal breast epithelium and Candia P et al

Other Information

Locus ID:

NCBI: 3400
MIM: 600581
HGNC: 5363
Ensembl: ENSG00000172201


dbSNP: 3400
ClinVar: 3400
TCGA: ENSG00000172201


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
TGF-beta signaling pathwayKEGGko04350
TGF-beta signaling pathwayKEGGhsa04350
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550


Pubmed IDYearTitleCitations
202019242010Genome-wide association study of alcohol dependence implicates a region on chromosome 11.159
197839862009The execution of the transcriptional axis mutant p53, E2F1 and ID4 promotes tumor neo-angiogenesis.81
215317662011ID4 imparts chemoresistance and cancer stemness to glioma cells by derepressing miR-9*-mediated suppression of SOX2.67
157230652005Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia.63
166824352006Inhibitors of differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett syndrome.51
186768082008Inhibitor of differentiation 4 drives brain tumor-initiating cell genesis through cyclin E and notch signaling.50
155699772004Epigenetic inactivation of ID4 in colorectal carcinomas correlates with poor differentiation and unfavorable prognosis.39
210983982011Silencing of the inhibitor of DNA binding protein 4 (ID4) contributes to the pathogenesis of mouse and human CLL.38
185133852008Promoter methylation-associated loss of ID4 expression is a marker of tumour recurrence in human breast cancer.37
185757652008Cdc42 is highly expressed in colorectal adenocarcinoma and downregulates ID4 through an epigenetic mechanism.35


Jean-Loup Huret

ID4 (inhibitor of DNA binding 4, dominant negative helix-loop-helix protein)

Atlas Genet Cytogenet Oncol Haematol. 2008-04-01

Online version: