Details for: WDR4

Gene ID: 10785

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: WDR4

Ensembl ID: ENSG00000160193

Description: WD repeat domain 4

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • stem cell CL0000034
    CSI 3.05
    rCSI 2.94%
    PRS 99.24
  • neural progenitor cell CL0011020
    CSI 2.69
    rCSI 11.83%
    PRS 95.95

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

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

Loading network (please wait)...

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 [WDR4](/details-gene/10785) (WD repeat domain 4) is a protein-coding gene located on chromosome 21q22.3. It functions as a key component and activator of the tRNA methyltransferase complex, playing an essential role in the post-transcriptional modification of transfer RNAs (tRNAs), specifically [tRNA (guanine-N7)-methylation](/details-go/GO:0106004). This function is critical for the broader processes of [tRNA processing](/details-reactome/R-HSA-72306) and the overall [Metabolism of RNA](/details-reactome/R-HSA-8953854). In addition to its role in RNA metabolism, [WDR4](/details-gene/10785) is also implicated in the [DNA damage response](/details-go/GO:0006974), suggesting a function in maintaining genomic stability. **Overall**, expression data indicate that [WDR4](/details-gene/10785) is a gene of high significance in progenitor populations, including [stem cell](/details-cell/CL0000034)s and [neural progenitor cell](/details-cell/CL0011020)s, consistent with its fundamental roles in cellular proliferation and maintenance. ## Cellular Roles and Expression Landscape The expression profile of [WDR4](/details-gene/10785) highlights its importance in highly proliferative and undifferentiated cell populations. **Overall**, the gene shows its highest significance in [stem cell](/details-cell/CL0000034) (CSI: 3.05) and [neural progenitor cell](/details-cell/CL0011020) (CSI: 2.69). This specific expression pattern suggests that the functions of [WDR4](/details-gene/10785), particularly in ensuring the fidelity of tRNA modification and responding to DNA damage, are crucial for supporting the rapid cell division and developmental potential characteristic of these cell types. Its role appears to be fundamental to the basic cellular machinery required for self-renewal and lineage commitment. ## Pathways and Molecular Function [WDR4](/details-gene/10785) is functionally annotated as a critical regulator of RNA metabolism. Its primary molecular function is as a [tRNA methyltransferase activator activity](/details-go/GO:0141106), where it acts as a non-catalytic subunit within the [tRNA (m7G46) methyltransferase complex](/details-go/GO:0106143) ([Link](https://pubmed.ncbi.nlm.nih.gov/12403464/)). This complex is responsible for the methylation of guanine at position 46 in certain tRNAs, a key step in [tRNA modification](/details-go/GO:0006400). These activities are integral to the Reactome pathways of [tRNA modification in the nucleus and cytosol](/details-reactome/R-HSA-6782315) and the broader [Metabolism of rna](/details-reactome/R-HSA-8953854). Beyond its role in RNA biology, [WDR4](/details-gene/10785) also participates in the [DNA damage response](/details-go/GO:0006974). Studies have shown it interacts with flap endonuclease 1 (FEN1), suggesting a role in maintaining genome stability ([Link](https://doi.org/10.1371/journal.pbio.1002349)). This dual involvement in both RNA processing and DNA integrity underscores its importance in fundamental cellular processes. The protein is found in multiple cellular compartments, including the [cytosol](/details-go/GO:0005829), [nucleoplasm](/details-go/GO:0005654), and broader [nucleus](/details-go/GO:0005634), consistent with its functions in both nuclear and cytosolic tRNA modification. ## Research Directions The established roles of [WDR4](/details-gene/10785) in tRNA modification and DNA damage response, combined with its high significance in progenitor cells, provide a foundation for several key research avenues. Mutations in [WDR4](/details-gene/10785) have been identified as a cause of Galloway-Mowat syndrome, a severe developmental disorder, highlighting the clinical relevance of its function ([Link](https://doi.org/10.1002/ajmg.a.40489)). **Proposed Testable Hypotheses:** 1. Given its high expression in [stem cell](/details-cell/CL0000034)s, dysregulation of [WDR4](/details-gene/10785)-mediated tRNA methylation may impair self-renewal by altering the translational efficiency of key pluripotency-associated transcripts. 2. The high significance of [WDR4](/details-gene/10785) in [neural progenitor cell](/details-cell/CL0011020)s suggests that its function in the [DNA damage response](/details-go/GO:0006974) is critical for preventing genomic instability during the rapid proliferation associated with neurogenesis. **Suggested Experimental Approach:** To test the first hypothesis regarding the role of [WDR4](/details-gene/10785) in stem cell biology, a CRISPR-Cas9-mediated knockout could be engineered in human induced pluripotent stem cells (iPSCs). The impact on self-renewal could be measured via long-term culture, proliferation assays, and analysis of pluripotency marker expression (e.g., OCT4, SOX2). To assess how its loss affects translational control, ribosome profiling (Ribo-seq) combined with tRNA sequencing (tRNA-seq) could be performed on wild-type and knockout iPSCs to identify specific mRNAs with altered translational efficiency and to confirm changes in the m7G tRNA modification landscape. **Therapeutic Potential:** [WDR4](/details-gene/10785) presents a complex therapeutic profile. Its fundamental role in cellular maintenance and high expression in healthy progenitor populations suggest that systemic inhibition could lead to significant toxicity, particularly in regenerative tissues. However, certain cancers exhibit a heightened dependency on specific tRNA pools and translational programs to support their high metabolic and proliferative rates. In such contexts, targeting [WDR4](/details-gene/10785) could represent a viable therapeutic strategy. Inhibition, likely via a small molecule inhibitor targeting its protein-protein interaction interface within the methyltransferase complex, could selectively compromise the viability of cancer cells that are uniquely vulnerable to perturbations in tRNA modification and translational fidelity.

Genular Protein ID: 2779875623

Symbol: WDR4_HUMAN

Name: N/A

UniProtKB Accession Codes:

P57081 A8KA58 B2RCA3 B4DNQ7 D3DSK3 Q9BVM5 Q9HCR3

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChiTaRS 1 ComplexPortal 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 12 EMDB 5 Ensembl 2 GO 11 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HAMAP 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 5 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 8 PDBsum 8 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 Pumba 1 RNAct 1 Reactome 1 RefSeq 6 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 10950928

Title: Isolation and characterization of a human chromosome 21q22.3 gene (WDR4) and its mouse homologue that code for a WD-repeat protein.

PubMed ID: 10950928

DOI: 10.1006/geno.2000.6258

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 10830953

Title: The DNA sequence of human chromosome 21.

PubMed ID: 10830953

DOI: 10.1038/35012518

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 12403464

Title: Two proteins that form a complex are required for 7-methylguanosine modification of yeast tRNA.

PubMed ID: 12403464

DOI: 10.1017/s1355838202024019

PubMed ID: 15861136

Title: The tRNA methylase METTL1 is phosphorylated and inactivated by PKB and RSK in vitro and in cells.

PubMed ID: 15861136

DOI: 10.1038/sj.emboj.7600648

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 20068231

Title: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.

PubMed ID: 20068231

DOI: 10.1126/scisignal.2000475

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 21406692

Title: System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation.

PubMed ID: 21406692

DOI: 10.1126/scisignal.2001570

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

DOI: 10.1021/pr300630k

PubMed ID: 26751069

Title: Wuho is a new member in maintaining genome stability through its interaction with flap endonuclease 1.

PubMed ID: 26751069

DOI: 10.1371/journal.pbio.1002349

PubMed ID: 30079490

Title: Mutations in WDR4 as a new cause of Galloway-Mowat syndrome.

PubMed ID: 30079490

DOI: 10.1002/ajmg.a.40489

PubMed ID: 31031084

Title: Transcriptome-wide mapping of internal N7-methylguanosine methylome in mammalian mRNA.

PubMed ID: 31031084

DOI: 10.1016/j.molcel.2019.03.036

PubMed ID: 31031083

Title: METTL1 promotes let-7 microRNA processing via m7G methylation.

PubMed ID: 31031083

DOI: 10.1016/j.molcel.2019.03.040

PubMed ID: 34352207

Title: METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation.

PubMed ID: 34352207

DOI: 10.1016/j.molcel.2021.06.031

PubMed ID: 34352206

Title: N7-Methylguanosine tRNA modification enhances oncogenic mRNA translation and promotes intrahepatic cholangiocarcinoma progression.

PubMed ID: 34352206

DOI: 10.1016/j.molcel.2021.07.003

PubMed ID: 34371184

Title: METTL1/WDR4-mediated m7G tRNA modifications and m7G codon usage promote mRNA translation and lung cancer progression.

PubMed ID: 34371184

DOI: 10.1016/j.ymthe.2021.08.005

PubMed ID: 37379838

Title: QKI shuttles internal m7G-modified transcripts into stress granules and modulates mRNA metabolism.

PubMed ID: 37379838

DOI: 10.1016/j.cell.2023.05.047

PubMed ID: 37369656

Title: Structural insight into how WDR4 promotes the tRNA N7-methylguanosine methyltransferase activity of METTL1.

PubMed ID: 37369656

DOI: 10.1038/s41421-023-00562-y

PubMed ID: 36599982

Title: Structures and mechanisms of tRNA methylation by METTL1-WDR4.

PubMed ID: 36599982

DOI: 10.1038/s41586-022-05565-5

PubMed ID: 36599985

Title: Structural basis of regulated m7G tRNA modification by METTL1-WDR4.

PubMed ID: 36599985

DOI: 10.1038/s41586-022-05566-4

PubMed ID: 26416026

Title: Mutation in WDR4 impairs tRNA m(7)G46 methylation and causes a distinct form of microcephalic primordial dwarfism.

PubMed ID: 26416026

DOI: 10.1186/s13059-015-0779-x

PubMed ID: 29597095

Title: Speech and language delay in a patient with WDR4 mutations.

PubMed ID: 29597095

DOI: 10.1016/j.ejmg.2018.03.007

PubMed ID: 28617965

Title: Further delineation of the phenotype caused by biallelic variants in the WDR4 gene.

PubMed ID: 28617965

DOI: 10.1111/cge.13074

Sequence Information:

  • Length: 412
  • Mass: 45490
  • Checksum: 394B11A2AFB1CADB
  • Sequence:
    • MAGSVGLALC GQTLVVRGGS RFLATSIASS DDDSLFIYDC SAAEKKSQEN KGEDAPLDQG 
SGAILASTFS KSGSYFALTD DSKRLILFRT KPWQCLSVRT VARRCTALTF IASEEKVLVA 
DKSGDVYSFS VLEPHGCGRL ELGHLSMLLD VAVSPDDRFI LTADRDEKIR VSWAAAPHSI 
ESFCLGHTEF VSRISVVPTQ PGLLLSSSGD GTLRLWEYRS GRQLHCCHLA SLQELVDPQA 
PQKFAASRIA FWCQENCVAL LCDGTPVVYI FQLDARRQQL VYRQQLAFQH QVWDVAFEET 
QGLWVLQDCQ EAPLVLYRPV GDQWQSVPES TVLKKVSGVL RGNWAMLEGS AGADASFSSL 
YKATFDNVTS YLKKKEERLQ QQLEKKQRRR SPPPGPDGHA KKMRPGEATL SC