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

Written2008-04Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)


HGNC (Hugo) ID4
HGNC Alias symbbHLHb27
HGNC Alias nameinhibitor of differentiation 4
HGNC Previous nameinhibitor of DNA binding 4, dominant negative helix-loop-helix protein
LocusID (NCBI) 3400
Atlas_Id 40916
Location 6p22.3  [Link to chromosome band 6p22]
Location_base_pair Starts at 19837370 and ends at 19842195 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping ID4.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ID4 (6p22.3)::FAM84A (2p24.3)NSD2 (4p16.3)::ID4 (6p22.3)STPG1 (1p36.11)::ID4 (6p22.3)


Description The gene spans 3,3 kb on plus strand.
Transcription 3 exons; mRNA 2,343 bp.


Description 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).
Expression Expressed in various tissues.
Function 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 B-cell acute lymphoblastic leukaemia (B-ALL) with --> ID4 - IGH
Note ID4 was juxtaposed to the IGH enhancer, leading to ID4 overexpression. (Bellido et al 2003, Russell et al 2008).
Prognosis Prognosis in this disease looks fair.
Entity Non Hodgkin lymphoma
Note 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 Brain tumours
Note In oligodendroglial tumours and glioblastomas, ID4 is expressed in neoplastic astrocytes but not in neoplastic oligodendrocytes (Liang et al, 2005).
Entity Breast cancer
Note 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 Bladder cancer
Note 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 Gastric cancer
Note ID4 promoter is hypermethylated and showed a low level of expression in 30% of gastric adenocarcinomas and in most gastric cancer cell lines, while it's 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 Colorectal cancer
Note 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 Rett syndrome
Note 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).


Id4 expression induces apoptosis in astrocytic cultures and is down-regulated by activation of the cAMP-dependent signal transduction pathway.
Andres-Barquin PJ, Hernandez MC, Israel MA.
Exp Cell Res. 1999 Mar 15;247(2):347-55.
PMID 10066362
Id4 is required for the correct timing of neural differentiation.
Bedford L, Walker R, Kondo T, van Cruchten I, King ER, Sablitzky F.
Dev Biol. 2005 Apr 15;280(2):386-95.
PMID 15882580
Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach.
Beger C, Pierce LN, Kruger M, Marcusson EG, Robbins JM, Welcsh P, Welch PJ, Welte K, King MC, Barber JR, Wong-Staal F.
Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):130-5.
PMID 11136250
Id4 is deregulated by a t(6;14)(p22;q32) chromosomal translocation in a B-cell lineage acute lymphoblastic leukemia.
Bellido M, Aventèn A, Lasa A, Estivill C, Carnicer MJ, Pons C, Matèas-Guiu X, Bordes R, Baiget M, Sierra J, Nomdedeu JF.
Haematologica. 2003 Sep;88(9):994-1001.
PMID 12969807
Downregulation of ID4 by promoter hypermethylation in gastric adenocarcinoma.
Chan AS, Tsui WY, Chen X, Chu KM, Chan TL, Chan AS, Li R, So S, Yuen ST, Leung SY.
Oncogene. 2003 Oct 9;22(44):6946-53.
PMID 14534543
Hormonal regulation and differential actions of the helix-loop-helix transcriptional inhibitors of differentiation (Id1, Id2, Id3, and Id4) in Sertoli cells.
Chaudhary J, Johnson J, Kim G, Skinner MK.
Endocrinology. 2001 May;142(5):1727-36.
PMID 11316735
Frequent DNA methylation but not mutation of the ID4 gene in malignant lymphoma.
Hagiwara K, Nagai H, Li Y, Ohashi H, Hotta T, Saito H.
J Clin Exp Hematop. 2007 Apr;47(1):15-8.
PMID 17510533
Id4 and FABP7 are preferentially expressed in cells with astrocytic features in oligodendrogliomas and oligoastrocytomas.
Liang Y, Bollen AW, Nicholas MK, Gupta N.
BMC Clin Pathol. 2005 Jul 15;5:6.
PMID 16018821
Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms.
Massari ME, Murre C.
Mol Cell Biol. 2000 Jan;20(2):429-40.
PMID 10611221
Inhibitors of differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett syndrome.
Peddada S, Yasui DH, LaSalle JM.
Hum Mol Genet. 2006 Jun 15;15(12):2003-14. Epub 2006 May 8.
PMID 16682435
The regulation and function of the Id proteins in lymphocyte development.
Rivera R, Murre C.
Oncogene. 2001 Dec 20;20(58):8308-16.
PMID 11840323
Tumoral expression of BRCA1, estrogen receptor alpha and ID4 protein in patients with sporadic breast cancer.
Roldan G, Delgado L, Muse IM.
Cancer Biol Ther. 2006 May;5(5):505-10. Epub 2006 May 13.
PMID 16582598
t(6;14)(p22;q32): a new recurrent IGHa translocation involving ID4 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Russell LJ, Akasaka T, Majid A, Sugimoto KJ, Loraine Karran E, Nagel I, Harder L, Claviez A, Gesk S, Moorman AV, Ross F, Mazzullo H, Strefford JC, Siebert R, Dyer MJ, Harrison CJ.
Blood. 2008 Jan 1;111(1):387-91.
PMID 17940204
Id4 regulates mammary epithelial cell growth and differentiation and is overexpressed in rat mammary gland carcinomas.
Shan L, Yu M, Qiu C, Snyderwine EG.
Am J Pathol. 2003 Dec;163(6):2495-502.
PMID 14633621
Aberrant hypermethylation of ID4 gene promoter region increases risk of lymph node metastasis in T1 breast cancer.
Umetani N, Mori T, Koyanagi K, Shinozaki M, Kim J, Giuliano AE, Hoon DS.
Oncogene. 2005 Jul 7;24(29):4721-7.
PMID 15897910
Epigenetic inactivation of ID4 in colorectal carcinomas correlates with poor differentiation and unfavorable prognosis.
Umetani N, Takeuchi H, Fujimoto A, Shinozaki M, Bilchik AJ, Hoon DS.
Clin Cancer Res. 2004 Nov 15;10(22):7475-83.
PMID 15569977
Amplification and overexpression of the ID4 gene at 6p22.3 in bladder cancer.
Wu Q, Hoffmann MJ, Hartmann FH, Schulz WA.
Mol Cancer. 2005 May 5;4(1):16.
PMID 15876350
Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia.
Yu L, Liu C, Vandeusen J, Becknell B, Dai Z, Wu YZ, Raval A, Liu TH, Ding W, Mao C, Liu S, Smith LT, Lee S, Rassenti L, Marcucci G, Byrd J, Caligiuri MA, Plass C.
Nat Genet. 2005 Mar;37(3):265-74.
PMID 15723065
Id4 regulates neural progenitor proliferation and differentiation in vivo.
Yun K, Mantani A, Garel S, Rubenstein J, Israel MA.
Development. 2004 Nov;131(21):5441-8. Epub 2004 Oct 6.
PMID 15469968
Id4 messenger RNA and estrogen receptor expression: inverse correlation in human normal breast epithelium and carcinoma.
de Candia P, Akram M, Benezra R, Brogi E.
Hum Pathol. 2006 Aug;37(8):1032-41. Epub 2006 May 22.
PMID 16867866


This paper should be referenced as such :
Huret, JL
ID4 (inhibitor of DNA binding 4, dominant negative helix-loop-helix protein)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(3):207-209.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 2 ]
  del(6p) (loss of JARID2 and DTNBP1) in myeloid malignances
t(6;14)(p22;q32) IGH::ID4

External links


HGNC (Hugo)ID4   5363
Entrez_Gene (NCBI)ID4    inhibitor of DNA binding 4, HLH protein
AliasesIDB4; bHLHb27
GeneCards (Weizmann)ID4
Ensembl hg19 (Hinxton)ENSG00000172201 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000172201 [Gene_View]  ENSG00000172201 [Sequence]  chr6:19837370-19842195 [Contig_View]  ID4 [Vega]
ICGC DataPortalENSG00000172201
TCGA cBioPortalID4
AceView (NCBI)ID4
Genatlas (Paris)ID4
SOURCE (Princeton)ID4
Genetics Home Reference (NIH)ID4
Genomic and cartography
GoldenPath hg38 (UCSC)ID4  -     chr6:19837370-19842195 +  6p22.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ID4  -     6p22.3   [Description]    (hg19-Feb_2009)
GoldenPathID4 - 6p22.3 [CytoView hg19]  ID4 - 6p22.3 [CytoView hg38]
Genome Data Viewer NCBIID4 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AI692586 AJ420553 AK130851 BC014941 DB461864
RefSeq transcript (Entrez)NM_001546
Consensus coding sequences : CCDS (NCBI)ID4
Gene ExpressionID4 [ NCBI-GEO ]   ID4 [ EBI - ARRAY_EXPRESS ]   ID4 [ SEEK ]   ID4 [ MEM ]
Gene Expression Viewer (FireBrowse)ID4 [ Firebrowse - Broad ]
GenevisibleExpression of ID4 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3400
GTEX Portal (Tissue expression)ID4
Human Protein AtlasENSG00000172201-ID4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP47928   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP47928  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP47928
Domaine pattern : Prosite (Expaxy)BHLH (PS50888)   
Domains : Interpro (EBI)bHLH_dom    DNA-bd_prot-inh    HLH_DNA-bd_sf   
Domain families : Pfam (Sanger)HLH (PF00010)   
Domain families : Pfam (NCBI)pfam00010   
Domain families : Smart (EMBL)HLH (SM00353)  
Conserved Domain (NCBI)ID4
AlphaFold pdb e-kbP47928   
Human Protein Atlas [tissue]ENSG00000172201-ID4 [tissue]
Protein Interaction databases
IntAct (EBI)P47928
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription by RNA polymerase II  negative regulation of transcription by RNA polymerase II  protein binding  nucleus  nucleus  nucleoplasm  nucleoplasm  cytoplasm  cell differentiation  circadian regulation of gene expression  negative regulation of transcription, DNA-templated  protein dimerization activity  transcription regulator activity  transcription regulator inhibitor activity  
Ontology : EGO-EBInegative regulation of transcription by RNA polymerase II  negative regulation of transcription by RNA polymerase II  protein binding  nucleus  nucleus  nucleoplasm  nucleoplasm  cytoplasm  cell differentiation  circadian regulation of gene expression  negative regulation of transcription, DNA-templated  protein dimerization activity  transcription regulator activity  transcription regulator inhibitor activity  
Pathways : KEGGTGF-beta signaling pathway   
NDEx NetworkID4
Atlas of Cancer Signalling NetworkID4
Wikipedia pathwaysID4
Orthology - Evolution
GeneTree (enSembl)ENSG00000172201
Phylogenetic Trees/Animal Genes : TreeFamID4
Homologs : HomoloGeneID4
Homology/Alignments : Family Browser (UCSC)ID4
Gene fusions - Rearrangements
Fusion : MitelmanID4::FAM84A [6p22.3/2p24.3]  
Fusion : MitelmanIGH::ID4 [14q32.33/6p22.3]  
Fusion : QuiverID4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerID4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ID4
Exome Variant ServerID4
GNOMAD BrowserENSG00000172201
Varsome BrowserID4
ACMGID4 variants
Genomic Variants (DGV)ID4 [DGVbeta]
DECIPHERID4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisID4 
ICGC Data PortalID4 
TCGA Data PortalID4 
Broad Tumor PortalID4
OASIS PortalID4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICID4  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DID4
Mutations and Diseases : HGMDID4
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)ID4
DoCM (Curated mutations)ID4
CIViC (Clinical Interpretations of Variants in Cancer)ID4
NCG (London)ID4
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry ID4
NextProtP47928 [Medical]
Target ValidationID4
Huge Navigator ID4 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDID4
Pharm GKB GenePA29611
Clinical trialID4
DataMed IndexID4
PubMed99 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:19:59 CEST 2021

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