FOXD4L6

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 41,126,435 bp [1] End 41,128,681 bp [1]
Gene location (Mouse) Chr. Chromosome 19 (mouse) [2] Band 19 B|19 19.86 cM Start 24,876,600 bp [2] End 24,878,561 bp [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
View/Edit Human View/Edit Mouse

Forkhead box D4 like 6 (FOXD4L6) is a protein in Homo sapiens encoded by the FOXD4L6 gene. As a member of the Forkhead box (FOX) transcription factor family it functions as a nuclear DNA-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. 9 p11.2
Search for Structures Swiss-model Domains InterPro

Gene identity

Genomic location of FOXD4L6 in chromosome 9

The gene lies within a FOXD4-like cluster and it has several neighboring loci, including FRG1HP, PGM5P2, LINC03025, and ZNG1F. ^[5]

mRNA transcript

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

Evolution and homology

Gene family context

FOXD4/FOXD4L Gene Family Phylogeny.

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]}

Unifying feature : the forkhead (FKH) domain

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

Homology

In vertebrates, the family diversified into more than ten subfamilies (FOXA–FOXS). The FOXD sub class includes FOXD1, FOXD2, FOXD3, and the FOXD4/FOXD4-like expansion present in primates. In humans, this expansion produced seven FOXD4L genes, including FOXD4L6. ^{[8] [7]}

Closely related paralogs 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 the N-terminus, a negatively charged “acidic blob” enriched in aspartic acid and glutamic acid contributes to protein–protein interaction surfaces. ^[7]

Protein and expression

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

Sub-cellular localization

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]

Tissue expression

Transcriptomic datasets, including GTEx and the Human 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]}

Regulatory features

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]

Variants and post translational modifications (PTMs)

A number of genetic 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]

FOXD4L6 Protein Schematic: PTMs, variants, motifs

Computational analyses predict several PTMs across the FOXD4L6 sequence:

• Phosphorylation at multiple serine, threonine, and tyrosine residues, especially within disordered regions. ^[7]
• Lysine and arginine 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]

Protein interactions

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

Abbreviated name	Full name	Basis of identification	Notes / Function
KIAA0232	KIAA0232 (uncharacterized protein)	Poorly characterized protein. Likely intracellular. Biological function unknown; interaction confidence low/medium	Unknown function
HSPBAP1	Heat shock protein-associated protein 1	Interacts with small heat-shock proteins (HSPB family). May be involved in protein folding or chaperone-associated regulation. Likely intracellular.	Suggests possible role in protein folding or stabilization.
ZNF496	Zinc finger protein 496	DNA-binding zinc-finger transcription factor. Nuclear localization matches FOXD4L6.	High confidence (compPASS) score; suggests transcriptional co-regulation.
ZBTB9	Zinc finger and BTB domain–containing 9	BTB/Zinc-finger transcription factor.	Also of nuclear localization.
FOXD2	Forkhead box protein D2	Member of the forkhead (FOX) transcription factor family.	High confidence score compPASS ~ 0.994
FBN2	Fibrillin-2	Extracellular matrix (ECM) structural protein.	Extracellular TFs, not consistent with FOXD4L6 localization

Clinical significance

Cancer-related expression

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

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

pLEC (primary pulmonary 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]

In thyroid 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]

Cell viability and immune-related responses

Functional genomic screens examining cytotoxicity and immune signaling place FOXD4L6 within immune-associated networks. ^[13]

In whole-genome RNAi screens using the immunotoxin SS1P, FOXD4L6 showed a subtle mitigator effect, suggesting a minor role in resistance to toxin-induced cell death. ^[13]

In septic acute kidney injury studies, FOXD4L6 is included among genes that are connected to pathways in T-cell activation, neutrophil signaling, and cytokine responses. ^[13]

Correlation studies revealed FOXD4L6 expression to be positively associated with CD8+ T-cell markers, hinting at a role in modulating tumor–immune interactions. ^[13]

References

1. GRCh38: Ensembl release 89: ENSG00000273514 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000051490 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "FOXD4L6 forkhead box D4 like 6 [Homo sapiens]". National Center for Biotechnology Information. Retrieved 2025-03-12.
6. "FOXD4L6 (HGNC:31986)". HUGO Gene Nomenclature Committee. Retrieved 2025-03-12.
7. "UniProtKB Q3SYB3 (FOXD4L6_HUMAN)". UniProt Consortium. Retrieved 2025-03-12.
8. Kaestner KH, Knochel W, Martinez DE (January 2000). "Unified nomenclature for the winged helix/forkhead transcription factors". Genes & Development. 14 (2): 142–146. doi:10.1101/gad.14.2.142. PMID   10702024.
9. Shimeld SM, Holland PW (April 2000). "Vertebrate innovations". Proceedings of the National Academy of Sciences of the United States of America. 97 (9): 4449–4452. doi: 10.1073/pnas.97.9.4449 . PMC   34320 . PMID   10781042.
10. "The Human Protein Atlas: FOXD4L6". Human Protein Atlas. Retrieved 2025-03-12.
11. "GTEx Portal: FOXD4L6". GTEx Consortium. Retrieved 2025-03-12.
12. Edgar R, Domrachev M, Lash AE (January 2002). "Gene Expression Omnibus: NCBI gene expression and hybridization array data repository". Nucleic Acids Research. 30 (1): 207–210. doi:10.1093/nar/30.1.207. PMID   11752295.
13. Wang T, Birsoy K, Hughes NW, Krupczak KM, Post Y, Wei JJ, et al. (November 2015). "Identification and characterization of essential genes in the human genome". Science. 350 (6264): 1096–1101. Bibcode:2015Sci...350.1096W. doi:10.1126/science.aac7041. PMC   4662922 . PMID   26472758.