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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)

Identity

Alias_namesinhibitor of DNA binding 4
Alias_symbol (synonym)bHLHb27
HGNC (Hugo) ID4
LocusID (NCBI) 3400
Atlas_Id 40916
Location 6p22.3  [Link to chromosome band 6p22]
Location_base_pair Starts at 19837601 and ends at 19842431 bp from pter ( according to hg19-Feb_2009)  [Mapping ID4.png]
Fusion genes
(updated 2016)
ID4 (6p22.3) / FAM84A (2p24.3)IGH (14q32.33) / ID4 (6p22.3)IGHG1 (14q32.33) / ID4 (6p22.3)

DNA/RNA

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

Protein

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

Note
Entity B-cell acute lymphoblastic leukaemia (B-ALL) with t(6;14)(p22;q32) --> 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).
  

Bibliography

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
 

Citation

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 ]
On line version : http://AtlasGeneticsOncology.org/Genes/ID4ID40916ch6p22.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(6;14)(p22;q32) IGH/ID4


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Lung: Translocations in Squamous Cell Carcinoma


External links

Nomenclature
HGNC (Hugo)ID4   5363
Cards
AtlasID4ID40916ch6p22
Entrez_Gene (NCBI)ID4  3400  inhibitor of DNA binding 4, HLH protein
AliasesIDB4; bHLHb27
GeneCards (Weizmann)ID4
Ensembl hg19 (Hinxton)ENSG00000172201 [Gene_View]  chr6:19837601-19842431 [Contig_View]  ID4 [Vega]
Ensembl hg38 (Hinxton)ENSG00000172201 [Gene_View]  chr6:19837601-19842431 [Contig_View]  ID4 [Vega]
ICGC DataPortalENSG00000172201
TCGA cBioPortalID4
AceView (NCBI)ID4
Genatlas (Paris)ID4
WikiGenes3400
SOURCE (Princeton)ID4
Genetics Home Reference (NIH)ID4
Genomic and cartography
GoldenPath hg19 (UCSC)ID4  -     chr6:19837601-19842431 +  6p22.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)ID4  -     6p22.3   [Description]    (hg38-Dec_2013)
EnsemblID4 - 6p22.3 [CytoView hg19]  ID4 - 6p22.3 [CytoView hg38]
Mapping of homologs : NCBIID4 [Mapview hg19]  ID4 [Mapview hg38]
OMIM600581   
Gene and transcription
Genbank (Entrez)AI692586 AJ420553 AK130851 BC014941 DB461864
RefSeq transcript (Entrez)NM_001546
RefSeq genomic (Entrez)NC_000006 NC_018917 NT_007592 NW_004929326
Consensus coding sequences : CCDS (NCBI)ID4
Cluster EST : UnigeneHs.663469 [ NCBI ]
CGAP (NCI)Hs.663469
Alternative Splicing GalleryENSG00000172201
Gene ExpressionID4 [ NCBI-GEO ]   ID4 [ EBI - ARRAY_EXPRESS ]   ID4 [ SEEK ]   ID4 [ MEM ]
Gene Expression Viewer (FireBrowse)ID4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3400
GTEX Portal (Tissue expression)ID4
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
Splice isoforms : SwissVarP47928
PhosPhoSitePlusP47928
Domaine pattern : Prosite (Expaxy)BHLH (PS50888)   
Domains : Interpro (EBI)bHLH_dom    DNA-bd_prot-inh   
Domain families : Pfam (Sanger)HLH (PF00010)   
Domain families : Pfam (NCBI)pfam00010   
Domain families : Smart (EMBL)HLH (SM00353)  
Conserved Domain (NCBI)ID4
DMDM Disease mutations3400
Blocks (Seattle)ID4
SuperfamilyP47928
Human Protein AtlasENSG00000172201
Peptide AtlasP47928
HPRD08995
IPIIPI00026864   
Protein Interaction databases
DIP (DOE-UCLA)P47928
IntAct (EBI)P47928
FunCoupENSG00000172201
BioGRIDID4
STRING (EMBL)ID4
ZODIACID4
Ontologies - Pathways
QuickGOP47928
Ontology : AmiGOG1/S transition of mitotic cell cycle  negative regulation of transcription from RNA polymerase II promoter  RNA polymerase II transcription factor binding  transcription corepressor activity  protein binding  nucleus  nucleus  cytoplasm  transcription, DNA-templated  regulation of transcription from RNA polymerase II promoter  neuroblast proliferation  circadian rhythm  positive regulation of cell proliferation  hippocampus development  cerebral cortex neuron differentiation  central nervous system myelination  cellular protein localization  fat cell differentiation  negative regulation of fat cell differentiation  negative regulation of neuron differentiation  positive regulation of osteoblast differentiation  negative regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  protein dimerization activity  negative regulation of astrocyte differentiation  negative regulation of oligodendrocyte differentiation  prostate gland epithelium morphogenesis  prostate gland stromal morphogenesis  seminal vesicle morphogenesis  
Ontology : EGO-EBIG1/S transition of mitotic cell cycle  negative regulation of transcription from RNA polymerase II promoter  RNA polymerase II transcription factor binding  transcription corepressor activity  protein binding  nucleus  nucleus  cytoplasm  transcription, DNA-templated  regulation of transcription from RNA polymerase II promoter  neuroblast proliferation  circadian rhythm  positive regulation of cell proliferation  hippocampus development  cerebral cortex neuron differentiation  central nervous system myelination  cellular protein localization  fat cell differentiation  negative regulation of fat cell differentiation  negative regulation of neuron differentiation  positive regulation of osteoblast differentiation  negative regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  protein dimerization activity  negative regulation of astrocyte differentiation  negative regulation of oligodendrocyte differentiation  prostate gland epithelium morphogenesis  prostate gland stromal morphogenesis  seminal vesicle morphogenesis  
Pathways : KEGGTGF-beta signaling pathway   
NDEx NetworkID4
Atlas of Cancer Signalling NetworkID4
Wikipedia pathwaysID4
Orthology - Evolution
OrthoDB3400
GeneTree (enSembl)ENSG00000172201
Phylogenetic Trees/Animal Genes : TreeFamID4
HOVERGENP47928
HOGENOMP47928
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]  [t(6;14)(p22;q32)]  
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerID4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ID4
dbVarID4
ClinVarID4
1000_GenomesID4 
Exome Variant ServerID4
ExAC (Exome Aggregation Consortium)ID4 (select the gene name)
Genetic variants : HAPMAP3400
Genomic Variants (DGV)ID4 [DGVbeta]
DECIPHER (Syndromes)6:19837601-19842431  ENSG00000172201
CONAN: Copy Number AnalysisID4 
Mutations
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]  
Mutations and Diseases : HGMDID4
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch ID4
DgiDB (Drug Gene Interaction Database)ID4
DoCM (Curated mutations)ID4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ID4 (select a term)
intoGenID4
NCG5 (London)ID4
Cancer3DID4(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM600581   
Orphanet
MedgenID4
Genetic Testing Registry ID4
NextProtP47928 [Medical]
TSGene3400
GENETestsID4
Huge Navigator ID4 [HugePedia]
snp3D : Map Gene to Disease3400
BioCentury BCIQID4
ClinGenID4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3400
Chemical/Pharm GKB GenePA29611
Clinical trialID4
Miscellaneous
canSAR (ICR)ID4 (select the gene name)
Probes
Litterature
PubMed70 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineID4
EVEXID4
GoPubMedID4
iHOPID4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Nov 18 19:57:42 CET 2016

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