CASZ1 (castor)
CASZ1 is the single human orthologue of Drosophila castor, a large multi-zinc-finger transcription factor that in flies specifies a late temporal window of neuroblast identity. The human gene sits at 1p36.22 and produces two main isoforms with different numbers of C2H2 zinc fingers. Its binding preference is poorly characterized: the only motif in these databases is a long, AT-rich composite model from in vitro selection, and no consensus has been established by focused biochemistry. CASZ1 is required for cardiac and vascular morphogenesis in Xenopus and mouse, its expression is low in high-risk neuroblastoma where 1p36 is frequently deleted, and common variants at the CASZ1 locus are among the earliest replicated blood-pressure associations.
The factors
CASZ1 (castor zinc finger 1, CST, ZNF693) is the vertebrate orthologue of Drosophila castor, which was cloned in 1992 as a novel zinc-finger protein required for the development of a subset of CNS neurons 1418995 and is best known as one of the temporal identity factors that mark a late window in neuroblast lineages. The human gene is at 1p36.22. It encodes a large protein with multiple C2H2 zinc fingers arranged in an unusual pattern, and two principal isoforms are described, commonly referred to by their finger counts (an eleven-finger and a five-finger form), which differ at the C terminus. CASZ1 binds DNA as a monomer as far as is known; no obligate dimerization partner has been reported, though it binds congenital heart disease protein 5 (CHD5, also called tryptophan-rich basic protein or WRB, a chromosome 21 gene unrelated to the chromodomain helicase CHD5) 24993940, and in retinal progenitors it associates with the NuRD nucleosome-remodelling complex 33594190. There is one human gene, so there is no paralogue problem within the family, but there is also very little comparative information to lean on. Expression is highest in heart, vasculature and neural-crest-derived sympathetic tissue, with additional expression in kidney and lung.
The motif
This family has no established consensus, and this entry does not invent one. The only model in these databases is a single HOCOMOCO matrix, CASZ1.H14CORE.0.SGI.A, with the data consensus TTTTGGGGNAAAATNNGNNDTTT - a 23-position, mostly AT-rich composite with two loosely specified blocks separated by a degenerate middle. Its evidence code (S, G, I) is three in vitro assays, HT-SELEX, GHT-SELEX and SMiLE-seq, and it carries a grade-A quality flag 41203846, so the measurement is credible as a measurement; what is missing is independent confirmation and any focused structural or mutational work assigning positions to particular fingers. There is no JASPAR, CIS-BP or Vierstra model for CASZ1 in this atlas, so cohesion is undefined (recorded as zero because there is nothing to compare against), and the motif's nearest neighbour in any other family reaches only about 0.64 similarity - it does not clearly resemble any other known element.
A long AT-rich model with a degenerate middle behaves in a scan much like a low-complexity filter. The information is spread thinly over many positions, poly-T and poly-A tracts will score, and the effective specificity is much lower than the length of the model suggests. Nothing is known about half-sites, spacing rules or which of the many CASZ1 zinc fingers contact DNA. Whether the two isoforms have different specificities has not been tested.
Where it acts
Direct, validated CASZ1 target genes are few. The best-characterized is EGFL7, which CASZ1 binds and activates in endothelial cells; CASZ1 depletion phenocopies EGFL7 loss in vascular sprouting, and restoring Egfl7 rescues the defect, acting through RhoA and focal-adhesion localization 23639441. In neuroblastoma cells, restoring CASZ1 changes the expression of a broad set of growth- and differentiation-related genes, but these were identified by expression profiling rather than by direct occupancy, so most are downstream rather than bound 21252912. Genome-wide occupancy maps for CASZ1 in human cells are sparse. The practical consequence is that there is no established picture of whether CASZ1 works from promoters or enhancers, what chromatin context its sites occupy, or which factors it co-occurs with. The literature here is thin and should be described as thin.
Biology and disease
CASZ1 is required for heart and blood-vessel development. In Xenopus, loss of CASZ1 blocks differentiation of cardiac precursor cells at the ventral midline 18410736, and CASZ1-depleted embryos fail to form a branched, lumenized vascular network; human endothelial cells depleted of CASZ1 show altered adhesion, morphology and sprouting 23639441. CASZ1 associates with CHD5 to maintain myocardial tissue integrity 24993940. In humans, a heterozygous CASZ1 missense variant (p.L38P) segregating with ventricular septal defect in one family was reported with reduced transactivation in reporter assays, the first link between CASZ1 and congenital heart disease 27693370; this rests on a single pedigree and should be treated as suggestive. In neuroblastoma, low CASZ1 expression correlates with older age at diagnosis, high-risk classification, 1p loss of heterozygosity and MYCN amplification, and with worse survival; restoring CASZ1 in neuroblastoma lines induces differentiation and suppresses tumorigenicity, making it a candidate for the 1p36 tumour suppressor 21252912. Separately, common variants at the CASZ1 locus were among the loci identified in early genome-wide association studies of blood pressure and hypertension 19430479, though the causal gene and mechanism at that locus have not been settled.
Reading a hit
Treat a CASZ1 match as weak. The model is a single long AT-rich composite from one database; there is no replication across databases, no structure, and no defined core, so a match does not license the conclusion that CASZ1 bound the sequence. AT-rich models of this shape also overlap the preferences of homeodomain, forkhead, HMG and other minor-groove AT readers, and they score poly-A/poly-T tracts, so sequence composition alone can produce hits. There is no paralogue ambiguity within the family, because there is only one gene, but that is not reassurance - it just means the usual family-versus-member caveat is replaced by a cruder one: the motif itself is not well enough established to support a specific call. Use a CASZ1 hit as a hypothesis to test with expression and occupancy data in a tissue where CASZ1 is actually expressed (heart, endothelium, sympathetic neuroblast lineage), and do not build an argument on the match alone.
How this was worked out
Drosophila castor is cloned in an enhancer-detection screen as a zinc-finger protein expressed in a subset of CNS neuroblasts and required for their development.
Still open then: No DNA-binding specificity was determined.
Vertebrate CASTOR (CASZ1) is shown to be required in Xenopus for differentiation of cardiac precursors at the ventral midline.
A CASZ1 variant (rs880315, P = 2.1 x 10^-7) is reported among the systolic blood pressure association signals of the CHARGE genome-wide association study.
Still open then: The signal fell short of conventional genome-wide significance (5 x 10^-8) in that study, and no causal gene was assigned.
Low CASZ1 expression in neuroblastoma correlates with high-risk features and poor survival, and restoring CASZ1 induces differentiation and suppresses tumorigenicity, nominating it as a 1p36 tumour suppressor.
Still open then: Responsive genes were found by expression profiling, not occupancy, so direct targets remained unknown.
- 2013mediumXenopus depletion; human endothelial cell knockdown; direct-target analysis; rescue23639441
CASZ1 is shown to directly regulate EGFL7 to promote vascular assembly; Egfl7 restores the defects of CASZ1-depleted endothelial cells.
CASZ1 is found to interact directly with congenital heart disease protein 5 (CHD5/WRB), and the interaction is needed for cardiac morphogenesis in Xenopus.
A heterozygous CASZ1 missense variant (p.L38P) co-segregating with ventricular septal defect in one family reduces transcriptional activity in reporter assays.
Still open then: A single pedigree; no replication.
Cross-platform data on poorly studied human transcription factors (HT-SELEX, genomic HT-SELEX and SMiLE-seq) underlie the first CASZ1 motif, the grade-A HOCOMOCO v14 model that is the only CASZ1 model in this atlas.
Still open then: No independent laboratory, mutational or structural work has yet tested the model or assigned it to particular fingers.
Still unresolved
- Whether the single CASZ1 model describes a defined recognition site or a broad AT-rich preference is unresolved: it is reproducible across three in vitro platforms, but no independent study, mutational analysis or structure has identified a core or tied positions to particular zinc fingers.
- Whether CASZ1 itself is the causal gene behind the blood-pressure association at its locus is unsettled: the association comes from genome-wide association data, and the cited work does not connect it to a CASZ1-dependent mechanism.
- Whether CASZ1 variants cause human congenital heart disease is unresolved: the p.L38P variant co-segregates with ventricular septal defect in one pedigree and reduces reporter activity, but no independent family has been reported in the cited work.
The whole family rests on one HOCOMOCO matrix, a 23-position AT-rich composite with a degenerate middle. Its evidence includes in vitro selection at grade A, so the measurement is credible, but there is no independent model in JASPAR, CIS-BP or Vierstra to corroborate it, cohesion is undefined, and no structural or mutational work assigns positions to specific zinc fingers. Long AT-rich models function partly as low-complexity filters: poly-A and poly-T tracts score, and the preferences overlap homeodomain, forkhead and HMG factors. Whether the two CASZ1 isoforms differ in specificity is untested. There is only one human gene, so no paralogue problem - but a match should be treated as a hypothesis, not an identification.
References
- Mellerick DM, Kassis JA, Zhang SD, et al. castor encodes a novel zinc finger protein required for the development of a subset of CNS neurons in Drosophila. Neuron 1992;9:789-803. PMID 1418995
- Christine KS, Conlon FL. Vertebrate CASTOR is required for differentiation of cardiac precursor cells at the ventral midline. Dev Cell 2008;14:616-23. PMID 18410736
- Levy D, Ehret GB, Rice K, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet 2009;41:677-87. PMID 19430479
- Liu Z, Yang X, Li Z, et al. CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression. Cell Death Differ 2011;18:1174-83. PMID 21252912
- Charpentier MS, Christine KS, Amin NM, et al. CASZ1 promotes vascular assembly and morphogenesis through the direct regulation of an EGFL7/RhoA-mediated pathway. Dev Cell 2013;25:132-43. PMID 23639441
- Sojka S, Amin NM, Gibbs D, et al. Congenital heart disease protein 5 associates with CASZ1 to maintain myocardial tissue integrity. Development 2014;141:3040-9. PMID 24993940
- Huang RT, Xue S, Wang J, et al. CASZ1 loss-of-function mutation associated with congenital heart disease. Gene 2016;595:62-68. PMID 27693370
- Yin Y, Morgunova E, Jolma A, et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science 2017;356. PMID 28473536
- 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
- Vorontsov IE, Kozin I, Abramov S, et al. Cross-platform motif discovery and benchmarking to explore binding specificities of poorly studied human transcription factors. Commun Biol 2025;8:1545. PMID 41203846
- Mattar P, Jolicoeur C, Dang T, et al. A Casz1-NuRD complex regulates temporal identity transitions in neural progenitors. Sci Rep 2021;11:3858. PMID 33594190
1 motifs in this family — HOCOMOCO 1
| motif | database | consensus | bits |
|---|---|---|---|
| CASZ1.H14CORE.0.SGI.ASGIA | HOCOMOCO | TTTTgGGgnaaAatnngnndtTT | 14.3 |
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.