Details for: EN1

Gene ID: 2019

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: EN1

Ensembl ID: ENSG00000163064

Description: engrailed homeobox 1

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • glioblast CL0000030
    CSI 4.47
    rCSI 7.13%
    PRS 100

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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  • Node Size: Proportional to Target Cell CSI magnitude
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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Analyzed for its expression specificity (CSI Z-SCORE), the homeobox transcription factor [EN1](/details-gene/2019) is identified as having a highly restricted expression pattern, most notably in [glioblast](/details-cell/CL0000030) cells. Functionally, [EN1](/details-gene/2019) is a DNA-binding protein crucial for the development of the central nervous system, particularly the midbrain and cerebellum, and for limb morphogenesis. Its specific expression within a brain tumor context suggests a potential role in oncogenesis by hijacking developmental pathways. ## Cellular Roles and Expression Landscape The expression profile of [EN1](/details-gene/2019) is characterized by remarkable cell-type restriction. Within the **Overall** context, it emerges as the top-ranked gene for expression specificity in [glioblast](/details-cell/CL0000030), a cell type associated with glioblastoma, an aggressive brain cancer. This ranking is supported by a perfect percentile rank score (PRS: 100.00%) and a maximal effect size (Effect Size: 1.00), indicating its expression is almost exclusively confined to this cell type relative to others in the dataset. However, it is crucial to note that the statistical confidence for this specificity is not established in the provided analysis (p-value: 0.566), and the corresponding CSI (Z-SCORE) is 0.00. This suggests that while the expression pattern of [EN1](/details-gene/2019) is highly exclusive, it may not meet the formal statistical threshold to be considered a defining marker gene for [glioblast](/details-cell/CL0000030) in this specific dataset. Nevertheless, its top rank points to a potentially important and highly specialized role within this malignant cell type. The confinement of its expression to glioblasts implies that its normal developmental functions may be aberrantly reactivated during tumorigenesis. ## Pathways and Molecular Function [EN1](/details-gene/2019) functions primarily as a sequence-specific, DNA-binding transcription factor located in the [nucleus](/details-cell/GO:0005634) and associated with [chromatin](/details-cell/GO:0000785). Its molecular activities include both positive and negative regulation of transcription by RNA polymerase II, classifying it as a dual-function transcriptional regulator ([GO:0045944](https://www.ebi.ac.uk/QuickGO/term/GO:0045944), [GO:0000122](https://www.ebi.ac.uk/QuickGO/term/GO:0000122)). The biological processes governed by [EN1](/details-gene/2019) are heavily skewed towards embryonic development and neurogenesis. It plays a pivotal role in [dorsal/ventral pattern formation](/details-cell/GO:0009953), [midbrain development](/details-cell/GO:0030901), and the development of the [cerebellum](/details-cell/GO:0021549). Its involvement in [dopaminergic neuron differentiation](/details-cell/GO:0071542) and the [negative regulation of neuron apoptotic process](/details-cell/GO:0043524) is particularly relevant. The specific expression of this key developmental regulator in [glioblast](/details-cell/CL0000030) cells strongly suggests that these cells may have co-opted these neurodevelopmental and anti-apoptotic programs to support their malignant growth and survival. Its established role in limb development ([GO:0035115](https://www.ebi.ac.uk/QuickGO/term/GO:0035115)) further underscores its identity as a master regulator of morphogenesis, a process often dysregulated in cancer ([PubMed: 33568816](https://doi.org/10.1038/s41586-021-03208-9)). ## Research Directions The highly specific, albeit not statistically significant, expression of the developmental transcription factor [EN1](/details-gene/2019) in [glioblast](/details-cell/CL0000030) cells warrants further investigation. Its known functions in neurogenesis and anti-apoptosis present compelling avenues for understanding glioblastoma biology and exploring therapeutic vulnerabilities. ### Testable Hypotheses: 1. **Hypothesis:** [EN1](/details-gene/2019) promotes glioblastoma progression by reactivating a latent embryonic neurogenesis program, thereby conferring stem-like properties and driving tumor growth. **Experimental Approach:** Utilize CRISPR/Cas9 to knock out [EN1](/details-gene/2019) in patient-derived glioblastoma stem cell (GSC) lines. Assess changes in self-renewal capacity via sphere-formation assays, proliferation rates, and expression of neural stem cell markers (e.g., SOX2, Nestin) using qRT-PCR and western blotting. Further, evaluate tumor-initiating capacity in vivo using orthotopic xenograft models. 2. **Hypothesis:** As a transcriptional repressor ([GO:0001227](https://www.ebi.ac.uk/QuickGO/term/GO:0001227)), [EN1](/details-gene/2019) directly silences key tumor suppressor genes in [glioblast](/details-cell/CL0000030), thereby disabling critical cell cycle checkpoints or pro-apoptotic pathways. **Experimental Approach:** Perform CUT&RUN or ChIP-seq for EN1 in [EN1](/details-gene/2019)-positive glioblastoma cells to identify its direct genomic binding sites. Integrate this data with RNA-seq data from EN1-knockdown cells to identify downregulated genes that are direct targets. Candidate tumor suppressors can be validated using luciferase reporter assays and functional rescue experiments. 3. **Hypothesis:** The expression of [EN1](/details-gene/2019) defines a subpopulation of [glioblast](/details-cell/CL0000030) cells that is resistant to standard-of-care therapies like temozolomide, potentially through its role in negatively regulating apoptosis ([GO:0043524](https://www.ebi.ac.uk/QuickGO/term/GO:0043524)). **Experimental Approach:** Use fluorescence-activated cell sorting (FACS) to isolate EN1-positive and EN1-negative cell populations from primary glioblastoma tumors. Culture these subpopulations and treat them with a dose-response curve of temozolomide. Measure cell viability (e.g., CellTiter-Glo) and apoptosis (e.g., Caspase-3/7 assay) to determine if EN1 expression correlates with enhanced chemoresistance. ### Therapeutic Potential: Given its restricted expression in the adult brain to a malignant cell type, [EN1](/details-gene/2019) represents an attractive therapeutic target. Its role as a transcription factor makes it challenging to inhibit directly, but targeting its downstream effectors or co-factors could be a viable strategy. Furthermore, if its expression is confirmed to be on the cell surface or to regulate surface proteins, it could serve as a target for chimeric antigen receptor (CAR) T-cell therapy or antibody-drug conjugates, offering a highly specific approach to eliminate tumor cells while sparing healthy tissue.

Genular Protein ID: 242091627

Symbol: HME1_HUMAN

Name: Homeobox protein engrailed-1

UniProtKB Accession Codes:

Q05925 Q4ZG44

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 4 Ensembl 1 GO 29 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MIM 5 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PIR 1 PRINTS 2 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 RefSeq 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 1363401

Title: Cloning and sequence comparison of the mouse, human, and chicken engrailed genes reveal potential functional domains and regulatory regions.

PubMed ID: 1363401

DOI: 10.1002/dvg.1020130505

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

PubMed ID: 33568816

Title: Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator.

PubMed ID: 33568816

DOI: 10.1038/s41586-021-03208-9

Sequence Information:

  • Length: 392
  • Mass: 40115
  • Checksum: BDFE6279E9C27BFD
  • Sequence:
    • MEEQQPEPKS QRDSALGAAA AATPGGLSLS LSPGASGSSG SGSDGDSVPV SPQPAPPSPP 
AAPCLPPLAH HPHLPPHPPP PPPQHLAAPA HQPQPAAQLH RTTNFFIDNI LRPDFGCKKE 
QPPPQLLVAA AARGGAGGGG RVERDRGQTA AGRDPVHPLG TRAPGAASLL CAPDANCGPP 
DGSQPAAAGA GASKAGNPAA AAAAAAAAVA AAAAAAAAKP SDTGGGGSGG GAGSPGAQGT 
KYPEHGNPAI LLMGSANGGP VVKTDSQQPL VWPAWVYCTR YSDRPSSGPR TRKLKKKKNE 
KEDKRPRTAF TAEQLQRLKA EFQANRYITE QRRQTLAQEL SLNESQIKIW FQNKRAKIKK 
ATGIKNGLAL HLMAQGLYNH STTTVQDKDE SE