SPZ1
SPZ1 is a single-gene family: one bHLH-Zip protein, with a basic helix-loop-helix domain followed by a leucine zipper, the same architecture as MYC, USF and the SREBPs. It was isolated from mouse testis, where expression is confined to testis and epididymis and is reduced by testosterone and retinoic acid. Unlike its palindrome-reading relatives, the one experimentally derived matrix is asymmetric, AGGGTAACAGC, from a small mouse SELEX experiment; the only other entry in the databases is a footprint archetype with a completely different, G-rich consensus. There is no ChIP-seq or in vitro human model. Overexpression studies link SPZ1 to MAPK-driven proliferation and transformation and to TWIST-mediated epithelial-mesenchymal transition in liver cancer.
The factors
SPZ1 (spermatogenic Zip 1) is a single gene with no human paralogues, and this family therefore has exactly one member. It was isolated from a mouse testis cDNA library and described as a bHLH-Zip protein: a basic helix-loop-helix domain followed by a leucine zipper, the same domain architecture as MYC, MAX, USF1/2, TFE3 and the SREBPs 11165476,10611221. In mouse, expression is restricted to testis and epididymis, with protein detected in the nuclei of Leydig cells, and transcript levels are reduced by testosterone and by retinoic acid 11165476. Nothing comparable to the structural, genetic and genomic literature that exists for the other bHLH families exists for SPZ1; there is no crystal structure, no knockout phenotype in the published record retrieved here, and no genome-wide binding map. The functional work that does exist is about overexpression: Spz1 driven downstream of mitogen-activated protein kinase signalling promotes proliferation, transformation of cultured cells and tumour formation in mice 15899793, and SPZ1 has since been reported to promote TWIST-mediated epithelial-mesenchymal transition in liver cancer 28368406, chemoresistance in breast cancer lines 30076850, and interleukin-6 induction in nasopharyngeal carcinoma cells 39440046. Whether endogenous human SPZ1 does any of this outside the testis is not established.
The motif
The family contains two entries, and they do not agree with each other.
The primary one is JASPAR MA0111.1, a SELEX-derived matrix for the mouse protein (UniProt Q99MY0), traceable to the original 2001 report, which described a nine-base asymmetric target site selected by random selection and PCR 37962376,11165476. The retrieved matrix is 11 columns wide and its column sums are 12, meaning it was built from about a dozen selected sequences — an extremely small sample by modern standards. Its consensus reads AGGGTAACAGC, with position 7 weakly A or T. Two things are worth noting about that string. It is asymmetric, unlike the palindromic CACGTG-type E-boxes that the other bHLH-Zip proteins read, and its 3' end, AACAGC, is the 5' half of a class A E-box with an A/T flank (AACAGCTG) but is not followed by a complete second half-site. Whether the selected element is a bona fide degenerate E-box variant or something else is not resolvable from one small SELEX experiment.
The second entry is the Vierstra archetype AC0575:SPZ:Unknown. Its consensus is GGRGGGT, a G-rich sequence with no resemblance to the SELEX model, and its structural class is recorded as unknown. Archetypes are named after whichever factor group dominated a cluster of footprint-derived motifs, so this is a claim about clustering, not about SPZ1 recognition 32728250. The two entries match each other poorly and match nothing else in the collection: the best similarity of either to any motif outside the family is 0.62 and 0.69 respectively, and family cohesion is 0.33, the lowest value in this part of the atlas. There is no HOCOMOCO model for SPZ1 at all — no ChIP-seq, no HT-SELEX, no methyl-SELEX — and no CIS-BP entry 25215497.
Where it acts
Unknown. With no ChIP-seq or footprint-verified model, there is no evidence in the collection about promoter versus enhancer preference, chromatin context, CpG association, typical occupancy count or co-occurring partners. The expectation for a bHLH-Zip protein would be dimerisation through the zipper and binding as a dimer, but SPZ1's dimerisation partner, if it has one, has not been identified in the material retrieved here.
Biology and disease
Restricted testis and epididymis expression in mouse, Leydig cell nuclear localisation, and downregulation by testosterone and retinoic acid are the only well-supported endogenous observations 11165476. A role in spermatogenesis was proposed on that basis but has not been demonstrated genetically in the literature retrieved. The cancer literature is overexpression-based: SPZ1 downstream of MAPK signalling drives proliferation, transformation and tumorigenesis in mouse models 15899793; SPZ1 promotes TWIST-mediated epithelial-mesenchymal transition and oncogenesis in human liver cancer 28368406; and reports link it to chemoresistance in drug-resistant breast cancer cells and to Wnt5a/interleukin-6 signalling in nasopharyngeal carcinoma 30076850,39440046. These are consistent in direction but come from a small literature centred on a few groups.
Reading a hit
Treat an SPZ1 match with real skepticism. The only sequence model with any experimental basis is a mouse SELEX matrix built from roughly twelve sequences, so its position weights are not well estimated, and using it on human sequence is a cross-species application even though the human and mouse proteins are orthologous. The only other entry, the SPZ archetype, is a different sequence entirely and is labelled with an unknown structural class, so the two cannot be reconciled. There is no in vitro human model and no ChIP evidence of any kind. In practice a hit to this family should be read as "the sequence resembles a poorly characterised mouse SELEX consensus", not as "SPZ1 binds here", and it should not be used to support a mechanistic claim without direct experimental follow-up. If SPZ1 came up as a top hit in a scan of human regulatory regions, the prior that the result is meaningful is low, and the prior that a better-supported factor explains the same sequence is high.
How this was worked out
The helix-loop-helix classes are set out in the form the atlas still uses, with the bHLH-Zip group (MYC, MAX, USF, TFE3, SREBP) defined by a leucine zipper appended to the bHLH and by dimeric binding to palindromic E-boxes — the class SPZ1 was later assigned to.
Spz1 is isolated from a mouse testis cDNA library as a bHLH-Zip protein expressed in testis and epididymis, with protein in Leydig cell nuclei and transcript reduced by testosterone and retinoic acid; random selection and PCR give a nine-base asymmetric target site, the matrix later deposited as JASPAR MA0111.1.
Still open then: The selected site rests on about a dozen sequences and was never confirmed by an independent assay, and no dimerization partner was identified.
Spz1 is placed downstream of mitogen-activated protein kinase signalling: overexpression promotes proliferation, transforms cultured cells and produces tumours in mice.
Still open then: Whether endogenous Spz1, whose expression is testis-restricted, does any of this was not addressed.
Successive genome-scale compilations leave SPZ1 essentially unmodelled: CIS-BP (2014) carries no SPZ1 motif, the human footprint archetypes (2020) place a G-rich cluster AC0575:SPZ:Unknown with unknown structural class, and JASPAR 2024 still offers only the 2001 mouse SELEX matrix.
Still open then: The archetype and the SELEX matrix are different sequences and no experiment reconciles them.
SPZ1 is reported to promote TWIST-mediated epithelial-mesenchymal transition and oncogenesis in human liver cancer, the first proposed mechanism for the human protein.
Still open then: Whether SPZ1 acts here through its own DNA binding or through protein-protein interaction with TWIST.
SPZ1 is linked to chemoresistance and aggressiveness in drug-resistant breast cancer cell lines.
SPZ1-mediated Wnt5a signalling is reported to induce interleukin-6 and promote progression in nasopharyngeal carcinoma cells, extending a small overexpression-based literature.
Still open then: No genome-wide binding map or knockout phenotype has yet been reported for SPZ1 in any system.
Still unresolved
- The family's two entries describe different sequences and cannot both be SPZ1's site: the mouse SELEX matrix reads AGGGTAACAGC while the footprint archetype AC0575:SPZ:Unknown reads a G-rich GGRGGGT, and no independent experiment exists to decide between them.
- Whether SPZ1 binds DNA as a homodimer, as a heterodimer with another bHLH-Zip protein, or chiefly through protein partners is unknown, since no dimerization partner has been identified and the selected site is asymmetric rather than palindromic like the sites read by other bHLH-Zip proteins.
- It is unresolved whether the selected element is a degenerate E-box variant at all: its 3' end, AACAGC, is the 5' half of a class A E-box with an A/T flank, but no complete second half-site follows, and one small selection experiment cannot settle the question.
- Whether endogenous human SPZ1 has any function outside the testis is unestablished: the proliferation, EMT, chemoresistance and interleukin-6 reports all rest on overexpression or knockdown in cell lines, and no knockout phenotype or genome-wide binding map has been published.
This is the weakest family in the batch and should be read as provisional. Its two motifs do not agree with each other: the JASPAR SELEX matrix (mouse, roughly twelve selected sequences) reads AGGGTAACAGC, while the Vierstra archetype AC0575:SPZ:Unknown reads a G-rich GGRGGGT and carries an unknown structural class. Cohesion is 0.33, and neither entry resembles anything else in the collection. There is no HOCOMOCO model at all for SPZ1 — no ChIP-seq, no HT-SELEX, no methyl-SELEX — and no CIS-BP entry, so nothing here establishes a human binding preference. A hit means the sequence resembles a small mouse SELEX consensus, nothing more.
References
- Hsu SH, Shyu HW, Hsieh-Li HM, et al. Spz1, a novel bHLH-Zip protein, is specifically expressed in testis. Mech Dev 2001;100:177-87. PMID 11165476
- Hsu SH, Hsieh-Li HM, Huang HY, et al. bHLH-zip transcription factor Spz1 mediates mitogen-activated protein kinase cell proliferation, transformation, and tumorigenesis. Cancer Res 2005;65:4041-50. PMID 15899793
- Wang LT, Chiou SS, Chai CY, et al. Transcription factor SPZ1 promotes TWIST-mediated epithelial-mesenchymal transition and oncogenesis in human liver cancer. Oncogene 2017;36:4405-4414. PMID 28368406
- Liu X, Han X, Wan X, et al. SPZ1 is critical for chemoresistance and aggressiveness in drug-resistant breast cancer cells. Biochem Pharmacol 2018;156:43-51. PMID 30076850
- Zeng X, Yang D, Li K, et al. Induction of interleukin-6 by SPZ1-mediated Wnt5a signaling boosts progression of nasopharyngeal carcinoma cells. J Cancer 2024;15:6148-6159. PMID 39440046
- Rauluseviciute I, Riudavets-Puig R, Blanc-Mathieu R, et al. JASPAR 2024: 20th anniversary of the open-access database of transcription factor binding profiles. Nucleic Acids Res 2024;52:D174-D182. PMID 37962376
- Vierstra J, Lazar J, Sandstrom R, et al. Global reference mapping of human transcription factor footprints. Nature 2020;583:729-736. PMID 32728250
- Weirauch MT, Yang A, Albu M, et al. Determination and inference of eukaryotic transcription factor sequence specificity. Cell 2014;158:1431-1443. PMID 25215497
- Massari ME, Murre C. Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol 2000;20:429-40. PMID 10611221
2 motifs in this family — JASPAR 1 · Vierstra 1
| motif | database | consensus | bits |
|---|---|---|---|
| Spz1 (MA0111.1) | JASPAR | AGGGTAaCAGC | 11.9 |
| AC0575:SPZ:Unknown | Vierstra | GGrGGGt | 8.2 |
HOCOMOCO tags read as assay + quality grade: P ChIP-seq, S HT-SELEX, M methyl-HT-SELEX, G GHT-SELEX, I SMiLE-seq, B PBM; grade A means two or more assay types agreed. A P-only matrix is a record of where the protein was crosslinked, which need not be a sequence it binds itself.
The factors, elsewhere
These entries are written from the primary literature and every citation is checked against PubMed, but this one can still be out of date, too confident, or simply wrong — especially where a motif’s published site and its database matrices disagree. Corrections and additions are welcome, and they are the fastest way to make this page better for everyone.