FOXD4L6
Identifiers
Aliases	FOXD4L6, forkhead box D4-like 6, forkhead box D4 like 6
External IDs	MGI:1347467;HomoloGene:129638;GeneCards:FOXD4L6;OMA:FOXD4L6 - orthologs
Gene location (Human) Chr. Chromosome 9 (human)[1] Band 9p11.2 Start 41,126,435bp[1] End 41,128,681bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19 B|19 19.86 cM Start 24,876,600bp[2] End 24,878,561bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right uterine tube Brodmann area 9 right frontal lobe hippocampus proper cerebellar hemisphere prefrontal cortex anterior cingulate cortex superior frontal gyrus right hemisphere of cerebellum nucleus accumbens Top expressed in granulocyte embryo hypoblast embryonic organizer red nucleus endoderm notochord spermatocyte mesoderm spinal ganglia More reference expression data BioGPS n/a
Gene ontology Molecular function DNA-binding transcription factor activity sequence-specific DNA binding DNA binding protein binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component nucleus Biological process regulation of transcription, DNA-templated transcription, DNA-templated regulation of transcription by RNA polymerase II anatomical structure morphogenesis cell differentiation Sources:Amigo /QuickGO
Orthologs Species Human Mouse Entrez 653404 14237 Ensembl ENSG00000273514 ENSMUSG00000051490 UniProt Q3SYB3 Q60688 RefSeq (mRNA) NM_001085476 NM_008022 RefSeq (protein) NP_001078945 NP_032048 Location (UCSC) Chr 9: 41.13 – 41.13 Mb Chr 19: 24.88 – 24.88 Mb PubMed search [3] [4]
Wikidata
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Forkhead box D4 like 6 (FOXD4L6) is a protein inHomo sapiens encoded by the FOXD4L6 gene. As a member of theForkhead box (FOX) transcription factor family it functions as a nuclearDNA-binding transcription factor.^[5][6][7]

Forkhead box D4-like 6
Predicted 3D structure of human FOXD4L6 highlighting the DNA-binding domain and overall fold
Identifiers
Symbol	FOXD4L6
HGNC	HGNC:31986
RefSeq	653404
UniProt	Q3SYB3
Other data
Locus	Chr. 9p11.2
Search for Structures Swiss-model Domains InterPro

The gene lies within a FOXD4-like cluster and it has several neighboring loci, includingFRG1HP,PGM5P2,LINC03025, andZNG1F.^[5]

Transcribed as a single-exon gene with nointrons; the gene FOXD4L6 produces one majormRNA transcript that is then translated into a chain of 417amino acids. Because the gene lacks introns, no alternative splicing orisoforms are reported.^[5][7]

FOXD4L6 belongs to the Forkhead box (FOX) gene family, an evolutionarily ancient group of transcription factors that originated in unicellular eukaryotes and expanded through multiple duplication events over the last 1.6 to 2.2 billion years.^[8][9]

The central FKH domain forms the double winged-helix structure responsible for DNA binding and shows the strongest conservation acrossvertebrates and invertebrates. In FOXD4L6, the forkhead DNA-binding region falls within the central portion, residue 108 to 202.^[7]

In vertebrates, the family diversified into more than ten subfamilies (FOXA–FOXS). TheFOXD sub class includesFOXD1,FOXD2,FOXD3, and theFOXD4/FOXD4-like expansion present in primates. In humans, this expansion produced sevenFOXD4L genes, including FOXD4L6.^[8][7]

Closely relatedparalogs were identified to be FOXD4, FOXD4L1–FOXD4L6, and more distantly FOXD1, FOXD2, and FOXD3. These paralogs display high sequence similarity, with the FOXD4-like members sharing ≥95% positive identity with FOXD4, and FOXD1/FOXD2/FOXD3 showing approximately 90% sequence identity to FOXD4L6.^[7]

Substantial residue identity was identified due to the highly conserved ~100-amino-acid forkhead (FKH) DNA-binding domain. Furthermore, other regions were identified; at theN-terminus, a negatively charged “acidic blob” enriched inaspartic acid andglutamic acid contributes to protein–protein interaction surfaces.^[7]

FOXD4L6 participates in transcriptional regulation via its forkhead domain and binds DNA in a sequence-specific manner.^[7]

Antibody-based proteomics data indicate that the FOXD4L6 protein localizes in the nuclei of the cell, with its predicted transcription factor role and chromatin association. No transmembrane segments or signal peptides are predicted, supporting nuclear residency without ER/Golgi trafficking.^[10]

Transcriptomic datasets, includingGTEx and theHuman Protein Atlas, show that FOXD4L6 expression is enriched in the brain, particularly in neural tissues derived from the embryonic ectoderm. Microarray datasets from GEO reveal substantial variability in expression across cancer and non-cancer cell lines, with little consistency among replicate lines of the same cancer type.^[11][10][12]

Analysis of the FOXD4L6 promoter reveals two promoter regions containing binding motifs for zinc-finger proteins, TFAP2 transcription factors, nuclear receptors, STAT-family factors, and RREB1.^[7]

A number ofgenetic variations can occur along the residues of this protein. At least 70 different genetic variations of the base pairs composition were registered to form synonymous modifications, which means the final protein composition was not affected by such edits. Somatic mutations were hypothesized to occur in residues: 3, 45, 108, 110, 118, 144, 145, 157, 185, 239, 280, 315, and 364.^[7]

Computational analyses predict several PTMs across the FOXD4L6 sequence:

• Phosphorylation at multipleserine,threonine, andtyrosine residues, especially within disordered regions.^[7]
• Lysine andarginine methylation at solvent-exposed residues outside the forkhead domain.^[7]
• An extended acidic region (residues ~19–44) corresponding to a high-scoring negatively charged segment, consistent with acidic domains found in chromatin-associated transcription factors.^[7]
• DNA methylation analyses in lung squamous cell carcinoma identify FOXD4L6 as an unusually methylated gene, consistent with altered states in cancer cells.^[12]

Table 1: Comparative table showing predicted protein-protein interactions of human FOXD4L6, including interaction type, confidence score, and functional relevance.

FOXD4L6 shows context-dependent expression across cancer.^[12]

Cancers likeglioma andskull base chordoma showed moderate expression of the protein. Others like lymphoma, thyroid, and head-and-neck cancers showed frequently high protein expression.^[12]

pLEC (primarypulmonary lymphoepithelial carcinoma): FOXD4L6 and related genes often show copy number gains and over expression, with survival analyses correlating lower FOXD4L6 expression with better prognosis.^[12]

Inthyroid carcinoma network analyses (CCMGDB), FOXD4L6 appears in normal-cell signaling networks but is absent from tumor-specific networks, consistent with down regulation in malignant tissue (tumor).^[12]

Functional genomic screens examiningcytotoxicity andimmune signaling place FOXD4L6 within immune-associated networks.^[13]

In whole-genomeRNAi screens using theimmunotoxinSS1P, FOXD4L6 showed a subtle mitigator effect, suggesting a minor role in resistance to toxin-induced cell death.^[13]

In septicacute kidney injury studies, FOXD4L6 is included among genes that are connected to pathways inT-cell activation,neutrophil signaling, andcytokine responses.^[13]

Correlation studies revealed FOXD4L6 expression to be positively associated withCD8+ T-cell markers, hinting at a role in modulating tumor–immune interactions.^[13]

• Genes on human chromosome 9
• Forkhead transcription factors

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• Short description is different from Wikidata
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