DLX2 (distal-less homeobox 2)

2014-03-01   Yorick Gitton  , Giovanni Levi  

Evolution des Regulations Endocriniennes, CNRS, UMR7221, Museum National dHistoire Naturelle, Paris, France

Identity

HGNC
DLX2
LOCATION
2q31.1
IMAGE
Atlas Image
LEGEND
Figure 1. Genomic context of the human DLX1/DLX2 bigenic locus.
LOCUSID
1746
ALIAS
TES-1,TES1
FUSION GENES
Show Gene Fusions

Abstract

DLX2 belongs to the six-member family of DLX genes characterized by a homeobox related to that found in the insect Distal-less (Dll) gene. It was the first human homologue to be discovered (Selski et al., 1993; McGuinness et al., 1996). The six DLX genes are organized as three bigenic pairs with a tail-to-tail orientation (Zerucha et al., 2000) and located on chromosomes where HOX clusters are also found (DLX5\/DLX6; 7q21.3, syntenic to the HOXA cluster), (DLX1\/DLX2; 2q32 syntenic to the HOXD cluster; Simeone et al., 1994; Zerucha et al., 2000) and (DLX3\/DLX4; 17q21.33 syntenic to the HOXB cluster). During embryonic development DLX genes are involved in the control of appendage and craniofacial morphogenesis and in the differentiation of reproductive organs; in the adult they play a role in bone homeostasis and in the maintenance of tissue integrity (Kraus and Lufkin, 2006).

DNA/RNA

Note

DLX2 is in an inverted convergent orientation from DLX1, with both exons 3 separated by 10.7 kb where two enhancers have been identified and functionally characterized (Zerucha et al., 2000; Sumiyama et al., 2002; Ghanem et al., 2003; Park et al., 2004). While one regulatory element is enough and sufficient to drive proper and full expression of Dlx1/Dlx2 genes based upon mouse reporter assays, other, extragenic elements are involved in the dual regulation of Dlx1 and Dlx2.
The imprinting status of the DLX1/DLX2 locus has received much less attention than that of their DLX5/DLX6 paralogs (see their respective cards). However, an epigenetic mechanism linking Dlx2 function with neural stem cell maintenance has been demonstrated in adult mice (Lim et al., 2009). Chromatin immunoprecipitation assays differentiating subventricular zone neural stem cells has shown that the Dlx2 locus is a direct bivalent target of the histone methyltransferase Mll1 (mixed-lineage leukemia 1). Whether such methylation process has a clinical relevance remains to be determined, as altered methylation of DLX2 has been observed in pathogenic conditions, including in primary cells from brain astrocytomas, where hypermethylation of DLX2 CpG island has been observed (Wu et al., 2010).
Atlas Image
Figure 2. The two known human DLX2 transcripts.

Transcription

Transcription from DLX2 yields two splice variants which share the first two exons, the homeodomain and the N-terminal DLL domain (see Figure 2). The major, mature isoform encodes a 328 AA long transcription factor (34.2 kDa and pI 9.25). Sense isoforms have not been reported for this gene.

Proteins

Atlas Image
Figure 3. Structure of the major DLX2 protein isoform. Note the N- and C-terminal poly-glycine stretches, and the N-terminal DLL-like domain.

Description

The major DLX2 isoform is a 328 AA helix-turn-helix homeodomain transcription factor (34.2 kDa and pI 9.5). The ultraconserved homeobox domain spans exons 1 and 2 at 153-211. A second N-terminal DNA binding domain, specific to the DLX2/3/5 clade within the distal-less family, is encoded by exon 1 at AA 51-132. Local composition biases include three poly-glycine and one poly-histidine stretches, and a phosphorylation target serine at 232 (see Figure 3 below).
Atlas Image
Figure 4. NCBI/COBALT alignment of DLX homeoproteins. Note the disposition according to the DLX 1/4/6 versus DLX 2/3/5 clades. Indicated by a yellow box is the ultraconserved glutamine featured by most homeoproteins at position 50 of the homeodomain.

Expression

DLX2 is a predominantly nuclear transcription factor, from the helix-turn-helix group. It transactivates target gene expression in heterodimeric association with other DLX and MSX transcription factors. Its consensus binding site is TTA(G/A)TTGA. Chromatin immunoprecitpitation assays have shown that during mouse forebrain development, Dlx2 (along with Dlx1) specifically binds an intergenic enhancer within the Dlx5/Dlx6 locus (see their respective cards), and transactivates their expression (Zerucha et al., 2000; Zhou et al., 2004). Interestingly, regulation of the Dlx5/Dlx6 locus in the developing retina occurs through transactivation by Dlx2 but not Dlx1.

Function

A particularity of Dlx2 is its ability to cooperate with a nuclear non-coding RNA (sense and single-stranded, 440 b), Evf-2, transcribed from the Dlx5/Dlx6 locus, to form a stable complex which binds and transactivates both Dlx5/6 intergenic enhancers (Feng et al., 2006). While such an RNA/homeoprotein cooperativity has been demonstrated for other factors (Dubnau and Struhl, 1996), it has not been reported so far for other Dlx family members.
On the other hand, Dlx2 has been shown to autorepress its expression during mouse tooth formation when expressed alone, while autoactivating it when expressed in combination with PitX2 (Venugopalan et al., 2011). This observation lends support to the notion that the transcriptional activity of DLX factors often depends upon cooperative binding with other homeproteins, including from the PTX and MSX families (Zhang et al., 1997; Vieux-Rochas et al., 2013).

Homology

With regards to other members of the DLX family, DLX2 belongs to the DLX2/3/5 clade based on sequence homology (see Figure 4). It shares an N-terminal DLL-like domain specific to this clade. The homeodomain sequence remains close to the other DLX proteins.

Implicated in

Entity name
Breast tumors and their metastases to bone and lung tissues
Note
Neoplastic processes often result from combinatorial activity of developmental genes (Abate-Shen, 2002). Dysregulated expression of homeobox-containing genes of the distal-less family, arranged as three bigenic pairs in mammals (DLX1/2, DLX3/4 and DLX5/6; Kraus and Lufkin, 2006), has been reported to correlate with distinct oncogenic mechanisms. DLX2 is expressed and necessary but insufficient to initiate metabolic stress-induced necrosis within several solid human high-grade tumors (Lee et al., 2011). DLX2 is strongly expressed in human primary breast tumors, its expression is associated with better prognosis and fewer relapses (Morini et al., 2010). In contrast, DLX2 expression is lost by breast tumor-derived metastatic cells found in lung or bone tissues - a poor prognosis marker (Morini et al., 2010). The combined downregulation of DLX2 and upregulation of DLX5 might thus prove a valuable prognostic marker.
DLX2 has been observed to be one of several homeogenes whose CpG islands were hypermethylated in luminal breast cancer cells, at 1 kb from the transcription start site (Kamalakaran et al., 2011). This status has been found to correlate significantly with higher expression level of DLX2, which lends support to the notion that DLX2 may serve as a candidate prognosis marker in breast cancer (Morini et al., 2010).
Entity name
Solid tumors involving other organs
Note
Induction of DLX2 expression has been further reported in other solid tumors, including promoting advanced gastric adenocarcinoma (Tang et al., 2013), promoting growth from lung, prostate and glioma tumors, and correlates with melanoma malignancy (Yilmaz et al., 2011; Yan et al., 2013). It appears that at least one member of each DLX bigenic pair (DLX2, DLX5 and DLX4 : see Hara et al., 2007) is closely implicated with solid tumorigenicty.
Entity name
Acute lymphoblastic leukemia
Note
Conversely, DLX2 expression is lost along with DLX3 and DLX4 in samples from patients afflicted by acute lymphoblastic leukemia with t(4;11)(q21;q23) chromosomal abnormality (Ferrari et al., 2003). In the same paper it is also shown that Dlx genes participate to the regulatory cascade initiated by acute lymphoblastic leukemia (ALL)-1, a recurring partner of translocations involving chromosome band 11q23 in human biphenotypic leukemias.
Entity name
Autism spectrum disorder
Note
Autism has been recognized as a condition which may result from an imbalance between inhibitory and excitatory processes in the developing and mature brain. Dlx1 and Dlx2 control the specification, fate and metabolic function of a subset of neurons known to exert an inhibitory role in the brain. As part of a cascade of homeobox-containing genes controlling neuronal specification in the brain, the DLX1/2 locus has thus been examined for association with autism spectrum disorder. Extensive coverage of both coding and intergenic sequences among a large cohort of autistic probands has uncovered only a handful of non-synonymous variants - which nevertheless provides a strong set of functional candidates to assess whether disrupted DLX2 expression might play a role in autism (Hamilton et al., 2005). More recently, a large cohort study has pinpointed stronger candidate sites of polymorphism correlated with increased susceptibility to develop the neurologic condition (Liu et al., 2009) - however a direct functional impact remains to be evidenced. Interestingly, DLX2 was found to harbour trinucleotide repeats but as for its DLX6 paralog, family-based association analysis ruled out this polymorphism as a risk variant, in either autism or schizophrenia patients (Laroche et al., 2008).
Entity name
Dysmorphogenesis
Note
Although mouse embryos invalidated for Dlx1 and/or Dlx2 display craniofacial abnormalities, a direct involvement of DLX1/DLX2 mutation in human malformations remains to be demonstrated. For instance, while synpolydactyly has been tightly linked to DLX2 (Sarfarazi et al., 1995), it is the lack of induction of its promoter by defective PITX2 which has been demonstrated to directly cause Axenfeld-Rieger syndrome (ARS, OMIM #180500) - an autosomal dominant condition featuring a wide range of tooth anomalies, maxillary hypoplasia, and eye malformation (Espinoza et al., 2002).

Article Bibliography

Pubmed IDLast YearTitleAuthors
123602802002Deregulated homeobox gene expression in cancer: cause or consequence?Abate-Shen C et al
86022141996RNA recognition and translational regulation by a homeodomain protein.Dubnau J et al
119298472002A molecular basis for differential developmental anomalies in Axenfeld-Rieger syndrome.Espinoza HM et al
167050372006The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator.Feng J et al
128859482003DLX genes as targets of ALL-1: DLX 2,3,4 down-regulation in t(4;11) acute lymphoblastic leukemias.Ferrari N et al
126709952003Regulatory roles of conserved intergenic domains in vertebrate Dlx bigene clusters.Ghanem N et al
162664342005Analysis of four DLX homeobox genes in autistic probands.Hamilton SP et al
174567652007A homeobox gene related to Drosophila distal-less promotes ovarian tumorigenicity by inducing expression of vascular endothelial growth factor and fibroblast growth factor-2.Hara F et al
211690702011DNA methylation patterns in luminal breast cancers differ from non-luminal subtypes and can identify relapse risk independent of other clinical variables.Kamalakaran S et al
166887242006Dlx homeobox gene control of mammalian limb and craniofacial development.Kraus P et al
190182352008Polymorphisms of coding trinucleotide repeats of homeogenes in neurodevelopmental psychiatric disorders.Laroche F et al
219171502011Homeobox gene Dlx-2 is implicated in metabolic stress-induced necrosis.Lee SY et al
192123232009Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells.Lim DA et al
187286932009The DLX1and DLX2 genes and susceptibility to autism spectrum disorders.Liu X et al
88124811996Sequence, organization, and transcription of the Dlx-1 and Dlx-2 locus.McGuinness T et al
211088122010Mutually exclusive expression of DLX2 and DLX5/6 is associated with the metastatic potential of the human breast cancer cell line MDA-MB-231.Morini M et al
150631872004Intergenic enhancers with distinct activities regulate Dlx gene expression in the mesenchyme of the branchial arches.Park BK et al
75813881995Localization of the syndactyly type II (synpolydactyly) locus to 2q31 region and identification of tight linkage to HOXD8 intragenic marker.Sarfarazi M et al
79011261993The human brain homeogene, DLX-2: cDNA sequence and alignment with the murine homologue.Selski DJ et al
79077941994Cloning and characterization of two members of the vertebrate Dlx gene family.Simeone A et al
117928342002Genomic structure and functional control of the Dlx3-7 bigene cluster.Sumiyama K et al
236748782013Increased expression of DLX2 correlates with advanced stage of gastric adenocarcinoma.Tang P et al
215049052011Hierarchical interactions of homeodomain and forkhead transcription factors in regulating odontogenic gene expression.Venugopalan SR et al
233828102013BMP-mediated functional cooperation between Dlx5;Dlx6 and Msx1;Msx2 during mammalian limb development.Vieux-Rochas M et al
202338742010CpG island hypermethylation in human astrocytomas.Wu X et al
233310162013Upregulation of DLX2 confers a poor prognosis in glioblastoma patients by inducing a proliferative phenotype.Yan ZH et al
218973652011Transcription factor Dlx2 protects from TGFβ-induced cell-cycle arrest and apoptosis.Yilmaz M et al
106326002000A highly conserved enhancer in the Dlx5/Dlx6 intergenic region is the site of cross-regulatory interactions between Dlx genes in the embryonic forebrain.Zerucha T et al
91113641997Heterodimerization of Msx and Dlx homeoproteins results in functional antagonism.Zhang H et al
147699462004Identification of a direct Dlx homeodomain target in the developing mouse forebrain and retina by optimization of chromatin immunoprecipitation.Zhou QP et al

Other Information

Locus ID:

NCBI: 1746
MIM: 126255
HGNC: 2915
Ensembl: ENSG00000115844

Variants:

dbSNP: 1746
ClinVar: 1746
TCGA: ENSG00000115844
COSMIC: DLX2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000115844ENST00000234198Q07687
ENSG00000115844ENST00000234198Q53QU7
ENSG00000115844ENST00000234198X5D7D8
ENSG00000115844ENST00000466293Q07687

Expression (GTEx)

0
1
2
3
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

References

Pubmed IDYearTitleCitations
372865192023JMJD3 is Involved in Intracranial Aneurysm Development by Regulating DLX2 Expression through H3K27me3 Modification.0
372865192023JMJD3 is Involved in Intracranial Aneurysm Development by Regulating DLX2 Expression through H3K27me3 Modification.0
363171402022DLX2 Is a Potential Immune-Related Prognostic Indicator Associated with Remodeling of Tumor Microenvironment in Lung Squamous Cell Carcinoma: An Integrated Bioinformatical Analysis.3
363171402022DLX2 Is a Potential Immune-Related Prognostic Indicator Associated with Remodeling of Tumor Microenvironment in Lung Squamous Cell Carcinoma: An Integrated Bioinformatical Analysis.3
321652912020DLX2 activates Wnt1 transcription and mediates Wnt/β-catenin signal to promote osteogenic differentiation of hBMSCs.13
329779482020Knockdown of circ_HIPK3 inhibits tumorigenesis of hepatocellular carcinoma via the miR-582-3p/DLX2 axis.10
321652912020DLX2 activates Wnt1 transcription and mediates Wnt/β-catenin signal to promote osteogenic differentiation of hBMSCs.13
329779482020Knockdown of circ_HIPK3 inhibits tumorigenesis of hepatocellular carcinoma via the miR-582-3p/DLX2 axis.10
308615842019Expression of ventral telencephalon transcription factors ASCL1 and DLX2 in the early fetal human cerebral cortex.14
308615842019Expression of ventral telencephalon transcription factors ASCL1 and DLX2 in the early fetal human cerebral cortex.14
281319102017Polymorphisms in genes involved in enamel development are associated with dental fluorosis.5
284594642017Bone morphogenetic protein signaling mediated by ALK-2 and DLX2 regulates apoptosis in glioma-initiating cells.18
292426282017Mutant Runx2 regulates amelogenesis and osteogenesis through a miR-185-5p-Dlx2 axis.21
281319102017Polymorphisms in genes involved in enamel development are associated with dental fluorosis.5
284594642017Bone morphogenetic protein signaling mediated by ALK-2 and DLX2 regulates apoptosis in glioma-initiating cells.18

Citation

Yorick Gitton ; Giovanni Levi

DLX2 (distal-less homeobox 2)

Atlas Genet Cytogenet Oncol Haematol. 2014-03-01

Online version: http://atlasgeneticsoncology.org/gene/52177/dlx2-(distal-less-homeobox-2)