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

2008-04-01 Jean-Loup Huret Affiliation

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

Identity

HGNC

ID4

LOCATION

6p22.3

LOCUSID

3400

ALIAS

IDB4,bHLHb27

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

The gene spans 3,3 kb on plus strand.

Transcription

3 exons; mRNA 2,343 bp.

Proteins

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 name

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 name

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 name

Brain tumours

Note

In oligodendroglial tumours and glioblastomas, ID4 is expressed in neoplastic astrocytes but not in neoplastic oligodendrocytes (Liang et al, 2005).

Entity name

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 name

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 name

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 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

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 name

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).

Article Bibliography

Pubmed ID	Last Year	Title	Authors
10066362	1999	Id4 expression induces apoptosis in astrocytic cultures and is down-regulated by activation of the cAMP-dependent signal transduction pathway.	Andres-Barquin PJ et al
15882580	2005	Id4 is required for the correct timing of neural differentiation.	Bedford L et al
11136250	2001	Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach.	Beger C et al
12969807	2003	Id4 is deregulated by a t(6;14)(p22;q32) chromosomal translocation in a B-cell lineage acute lymphoblastic leukemia.	Bellido M et al
14534543	2003	Downregulation of ID4 by promoter hypermethylation in gastric adenocarcinoma.	Chan AS et al
11316735	2001	Hormonal 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
17510533	2007	Frequent DNA methylation but not mutation of the ID4 gene in malignant lymphoma.	Hagiwara K et al
16018821	2005	Id4 and FABP7 are preferentially expressed in cells with astrocytic features in oligodendrogliomas and oligoastrocytomas.	Liang Y et al
10611221	2000	Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms.	Massari ME et al
16682435	2006	Inhibitors of differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett syndrome.	Peddada S et al
11840323	2001	The regulation and function of the Id proteins in lymphocyte development.	Rivera R et al
16582598	2006	Tumoral expression of BRCA1, estrogen receptor alpha and ID4 protein in patients with sporadic breast cancer.	Roldán G et al
17940204	2008	t(6;14)(p22;q32): a new recurrent IGH@ translocation involving ID4 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).	Russell LJ et al
14633621	2003	Id4 regulates mammary epithelial cell growth and differentiation and is overexpressed in rat mammary gland carcinomas.	Shan L et al
15897910	2005	Aberrant hypermethylation of ID4 gene promoter region increases risk of lymph node metastasis in T1 breast cancer.	Umetani N et al
15569977	2004	Epigenetic inactivation of ID4 in colorectal carcinomas correlates with poor differentiation and unfavorable prognosis.	Umetani N et al
15876350	2005	Amplification and overexpression of the ID4 gene at 6p22.3 in bladder cancer.	Wu Q et al
15723065	2005	Global 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
15469968	2004	Id4 regulates neural progenitor proliferation and differentiation in vivo.	Yun K et al
16867866	2006	Id4 messenger RNA and estrogen receptor expression: inverse correlation in human normal breast epithelium and carcinoma.	de Candia P et al

Other Information

Locus ID:

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

Variants:

dbSNP: 3400
ClinVar: 3400
TCGA: ENSG00000172201
COSMIC: ID4

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000172201	ENST00000378700	P47928

Expression (GTEx)

100

150

200

250

300

350

400

450

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
TGF-beta signaling pathway	KEGG	ko04350
TGF-beta signaling pathway	KEGG	hsa04350
Signaling pathways regulating pluripotency of stem cells	KEGG	hsa04550
Signaling pathways regulating pluripotency of stem cells	KEGG	ko04550

References

Pubmed ID	Year	Title	Citations
38188675	2023	ELK3-ID4 axis governs the metastatic features of triple negative breast cancer.	0
38188675	2023	ELK3-ID4 axis governs the metastatic features of triple negative breast cancer.	0
35094293	2022	CDC42 as an epigenetic regulator of ID4 in triple-negative breast tumors.	1
35656024	2022	Upregulated circTMEM59 Inhibits Cell Growth and Metastasis by miR-668-3p/ID4 Axis in Colorectal Cancer.	7
35908351	2022	Osteoglycin (OGN) promotes tumorigenesis of pancreatic cancer cell via targeting ID4.	0
35094293	2022	CDC42 as an epigenetic regulator of ID4 in triple-negative breast tumors.	1
35656024	2022	Upregulated circTMEM59 Inhibits Cell Growth and Metastasis by miR-668-3p/ID4 Axis in Colorectal Cancer.	7
35908351	2022	Osteoglycin (OGN) promotes tumorigenesis of pancreatic cancer cell via targeting ID4.	0
33993270	2021	ID4 predicts poor prognosis and promotes BDNF-mediated oncogenesis of colorectal cancer.	7
34723712	2021	miR-9-5p Promotes Lung Adenocarcinoma Cell Proliferation, Migration and Invasion by Targeting ID4.	6
33993270	2021	ID4 predicts poor prognosis and promotes BDNF-mediated oncogenesis of colorectal cancer.	7
34723712	2021	miR-9-5p Promotes Lung Adenocarcinoma Cell Proliferation, Migration and Invasion by Targeting ID4.	6
32054109	2020	Paracrine Signaling from Breast Cancer Cells Causes Activation of ID4 Expression in Tumor-Associated Macrophages.	7
32527287	2020	Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer.	6
32574963	2020	UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymes.	17

Citation

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: http://atlasgeneticsoncology.org/gene/40916/gene-explorer/teaching-explorer/hgnc