OVOL (OVO-like)
OVOL1 and OVOL2 are C2H2 zinc-finger repressors, the mammalian counterparts of Drosophila OVO/shavenbaby, that bind a short AT-flanked core, CCGTTA (equivalently TAACGG on the other strand). They act mainly as repressors of the epithelial-to-mesenchymal transition, holding epithelial cells in an epithelial state by shutting down ZEB1, ZEB2 and other EMT inducers, and OVOL1 additionally represses its own promoter and MYC. Mouse knockouts show defects in hair follicles, sperm, kidney, mammary ductal morphogenesis and epidermal progenitor arrest. In humans, a promoter point mutation that mis-expresses OVOL2 in corneal endothelium causes posterior polymorphous corneal dystrophy type 1. OVOL1 and OVOL2 share one motif and cannot be separated from sequence.
The factors
The OVOL genes are the vertebrate orthologues of Drosophila ovo/shavenbaby (svb), a single locus whose alternative transcripts supply two genetic functions: svb for the extracellular projections of epidermal cells and ovo for female germ-cell survival 9808631,10637336. Humans have OVOL1 (11q13) and OVOL2 (20p11). A third gene, OVOL3, is annotated in some species but has no measured motif in these databases and is not represented here. The proteins carry four C2H2 zinc fingers, of which only about three contribute to specificity 10637336, and they bind DNA as monomers. OVOL1 and OVOL2 are epithelial: skin and hair follicle, kidney, mammary and corneal epithelium, placenta, and germ cells. Both act predominantly as transcriptional repressors; OVOL1 represses by competing with the activator MYB at overlapping sites and by recruiting histone deacetylase activity 17311813, and OVOL2 exists in repressor and non-repressor isoforms whose balance sets its output 24735879.
The motif
The consensus is CCGTTA, usually written with AT-rich flanks, and it appears in these databases in both orientations: ACCGTTAT (JASPAR OVOL1 and OVOL2) 28473536 and TAACGGT (HOCOMOCO OVOL2, and the atlas representative). These are the same element read on opposite strands, so the apparent disagreement between AT-rich and CG-containing renderings is only a strand convention. The information sits almost entirely on the six-base core; the flanking A/T positions add affinity but little specificity, which is why the shortest matrices here carry only about 6 bits.
The site was first defined by random-oligomer selection with the Drosophila OVO zinc-finger array, which gave a statistically significant 9-bp consensus and showed that the recognition does not follow the usual zinc-finger contact rules, consistent with the conclusion that some fingers in the array have degenerated and no longer read bases 10637336. Mouse Ovol1 binding sites in genomic DNA converge on the same CCGTTA core 16636146,17311813, and in OVO ChIP-seq from the Drosophila female germline the top peak motif, TAACGGTAAA, contains the same core on the other strand, although the authors define the core more permissively as TAACNGT 39291827; the core is conserved from fly to mouse. The permissive hexamer CC/TGTTA is also reported, with high-affinity sites favouring AT-rich flanks 17311813.
OVOL1 and OVOL2 are not distinguishable from sequence. Their matrices in all four databases converge (family cohesion about 0.89, and the best cross-member similarities exceed 0.98), so a hit identifies the family, not the member. One Vierstra archetype in this family, ACAGTTACA 32728250, is a variant with a different third position and does not match the others closely; treat it as a separate, weakly supported model.
Where it acts
OVOL sites are found in promoters and enhancers of epithelial-identity and EMT genes. Documented direct targets include ZEB1 and other EMT inducers 24124593,24735879, MYC (repressed by OVOL1 in embryonic epidermal progenitors) 16636146, the OVOL1 promoter itself 17311813, and in flies the ovarian tumor (otu) promoter, where OVO binds unusually close to the transcription start site 11290304. That proximity to start sites is a recurring feature: OVO/OVOL sites cluster near TSSs rather than in distal enhancer deserts 39291827. In epithelial cells the factors sit inside a double-negative feedback loop with ZEB1/ZEB2 24124593,24735879, so OVOL peaks tend to co-occur with ZEB and SNAI motifs in the same regulatory regions, and with GRHL and KLF4 motifs that mark epithelial promoters. The core is only 6 bp, so genomic occurrences are numerous in any sequence composition.
Biology and disease
Mouse Ovol1 (movo1) knockouts are small, make aberrant hairs, show hypogenitalism with reduced fertility and develop kidney abnormalities 9808631; the epidermal phenotype traces to failure of embryonic epidermal progenitors to arrest and to de-repression of MYC 16636146. Ovol2 deletion blocks mammary ductal morphogenesis, depletes stem and progenitor pools, and lets epithelial cells undergo EMT in vivo; conversely, forced expression of the repressor isoform of OVOL2 reverts metastatic breast cancer cells toward an epithelial state 24735879. OVOL1 and OVOL2 can both induce mesenchymal-to-epithelial transition in human cancer cell lines 24124593. In human disease, posterior polymorphous corneal dystrophy type 1 is caused by point mutations in the OVOL2 promoter (c.-307T>C and related variants) that switch the gene on ectopically in corneal endothelium 26749309,28046031, and OVOL2 maintains the corneal epithelial program by suppressing EMT 27134177. Reports in lung, colorectal and breast cancer describe both tumour-suppressive and context-dependent pro-tumour effects, and the literature here is not settled.
Reading a hit
CCGTTA is six informative bases, so chance matches are frequent: expect many hits per megabase and treat a single match as weak evidence. Sequence cannot distinguish OVOL1 from OVOL2, and in most epithelial tissues both are expressed, so ChIP-seq in such a cell will not resolve them either. The evidence base for this family is comparatively good: the HOCOMOCO OVOL1 and OVOL2 models carry in vitro support (HT-SELEX and methyl-SELEX) 28473536, so "this protein binds this sequence" is well established even though "this sequence was bound by this protein here" is not. Be alert to the reverse-complement rendering TAACGGT, which is the same site and is easy to mistake for an unrelated motif. A match in an EMT-associated promoter alongside ZEB or SNAI sites is more interpretable than an isolated hit, but the direction of effect still has to come from expression or perturbation data.
How this was worked out
A mouse ovo orthologue, movo1 (Ovol1), is cloned; knockout mice are small, make aberrant hairs, have reduced fertility and kidney abnormalities, paralleling the fly epidermal and germline functions.
Still open then: The sequence bound by the vertebrate protein was not known.
Random-oligomer selection with the Drosophila OVO zinc-finger array gives a 9-bp consensus that matches sites in known target genes but breaks the usual zinc-finger contact rules; only three of the four fingers appear to contribute.
OVO is shown to activate ovarian tumor (otu) through a site unusually close to the transcription start, establishing a direct target and a TSS-proximal mode of action.
- 2006mediumKnockout epidermis analysis; EMSA; ChIP; CAST site selection; reporter assays16636146 17311813
Mouse Ovol1 is shown to bind CCGTTA sites to repress c-myc and its own promoter; site selection with recombinant Ovol1 then gives an AT-flanked CYGTTA consensus, and repression combines competition with c-Myb and HDAC recruitment.
- 2014mediumConditional knockout mice; target binding and expression analysis; forced-expression reprogramming24735879
Ovol2 is required for mammary ductal morphogenesis, where it directly represses EMT inducers; its repressor isoform can push metastatic breast cancer cells back to an epithelial state.
- 2016highLinkage, targeted and whole-genome sequencing in large pedigrees; reporter assays26749309 28046031
Non-coding mutations in the OVOL2 proximal promoter are found to cause the corneal endothelial dystrophies CHED1 and PPCD1, increasing promoter activity in a tissue where OVOL2 is normally not detected.
Still open then: Which factor acts on the mutated promoter to switch OVOL2 on was not identified.
HT-SELEX and methyl-SELEX with human OVOL1 and OVOL2 yield the ACCGTTA-type models now used in JASPAR and HOCOMOCO, confirming the core in vitro for both paralogues.
Genome-wide ChIP-seq of OVO in the Drosophila female germline finds binding concentrated near transcription start sites of essential maternal genes, with a TAACNGT motif that is degenerate at a position the vertebrate matrices fix.
Still open then: Whether the degenerate position reflects a real difference between fly and vertebrate proteins or a ChIP-versus-SELEX difference is untested.
Still unresolved
- How strict the second base of the core is remains unsettled: human in vitro matrices give CCGTTA, mouse Ovol1 site selection allowed C or T there (CYGTTA), and Drosophila OVO ChIP-seq gave TAACNGT, which would also admit the CAGTTA variant seen in the Vierstra ACAGTTACA archetype that this atlas treats as a separate, weakly supported model.
- Whether OVOL2 restrains or promotes carcinoma progression is not settled: it induces mesenchymal-to-epithelial transition and reduces metastatic potential in prostate and breast models, while reports in lung, colorectal and breast cancer also describe context-dependent pro-tumour effects.
- How the OVOL2 promoter mutations in PPCD1 and CHED1 cause disease is not established: they raise promoter activity and are proposed to create cryptic regulatory sites that switch OVOL2 on ectopically in corneal endothelium, but the factor that binds them has not been identified.
The informative core is only 6 bp (CCGTTA / TAACGG), so chance matches are abundant and one hit is weak evidence. OVOL1 and OVOL2 share a single motif - cohesion here is about 0.89 with cross-member similarities above 0.98 - so a match identifies the family, not the member, and ChIP in epithelium cannot separate them either because both are usually expressed. The two strand renderings (ACCGTTAT and TAACGGT) are the same element and are often mistaken for different motifs. Evidence quality is good: the OVOL1 and OVOL2 HOCOMOCO models include in vitro HT-SELEX and methyl-SELEX support. The Vierstra ACAGTTACA archetype is a poorly matching variant and should be treated separately.
References
- Dai X, Schonbaum C, Degenstein L, et al. The ovo gene required for cuticle formation and oogenesis in flies is involved in hair formation and spermatogenesis in mice. Genes Dev 1998;12:3452-63. PMID 9808631
- Lee S, Garfinkel MD. Characterization of Drosophila OVO protein DNA binding specificity using random DNA oligomer selection suggests zinc finger degeneration. Nucleic Acids Res 2000;28:826-34. PMID 10637336
- Lü J, Oliver B. Drosophila OVO regulates ovarian tumor transcription by binding unusually near the transcription start site. Development 2001;128:1671-86. PMID 11290304
- Nair M, Teng A, Bilanchone V, et al. Ovol1 regulates the growth arrest of embryonic epidermal progenitor cells and represses c-myc transcription. J Cell Biol 2006;173:253-64. PMID 16636146
- Jolma A, Yan J, Whitington T, et al. DNA-binding specificities of human transcription factors. Cell 2013;152:327-39. PMID 23332764
- Roca H, Hernandez J, Weidner S, et al. Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer. PLoS One 2013;8:e76773. PMID 24124593
- Watanabe K, Villarreal-Ponce A, Sun P, et al. Mammary morphogenesis and regeneration require the inhibition of EMT at terminal end buds by Ovol2 transcriptional repressor. Dev Cell 2014;29:59-74. PMID 24735879
- Kitazawa K, Hikichi T, Nakamura T, et al. OVOL2 Maintains the Transcriptional Program of Human Corneal Epithelium by Suppressing Epithelial-to-Mesenchymal Transition. Cell Rep 2016;15:1359-68. PMID 27134177
- Chung DD, Frausto RF, Cervantes AE, et al. Confirmation of the OVOL2 Promoter Mutation c.-307T>C in Posterior Polymorphous Corneal Dystrophy 1. PLoS One 2017;12:e0169215. PMID 28046031
- 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
- Benner L, Muron S, Gomez JG, et al. OVO positively regulates essential maternal pathways by binding near the transcriptional start sites in the Drosophila female germline. Elife 2024;13. PMID 39291827
- Vierstra J, Lazar J, Sandstrom R, et al. Global reference mapping of human transcription factor footprints. Nature 2020;583:729-736. PMID 32728250
- Nair M, Bilanchone V, Ortt K, et al. Ovol1 represses its own transcription by competing with transcription activator c-Myb and by recruiting histone deacetylase activity. Nucleic Acids Res 2007;35:1687-97. PMID 17311813
- Davidson AE, Liskova P, Evans CJ, et al. Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2. Am J Hum Genet 2016;98:75-89. PMID 26749309
9 motifs in this family — JASPAR 2 · HOCOMOCO 2 · CIS-BP 2 · Vierstra 3
| motif | database | consensus | bits |
|---|---|---|---|
| OVOL1.H14CORE.0.SM.BSMB | HOCOMOCO | anATAACGGT | 15.7 |
| M04556_2.00 | CIS-BP | aaACCGTTATnt | 15.2 |
| OVOL1 (MA1544.2) | JASPAR | aaACCGTTAT | 14.5 |
| OVOL2.H14CORE.0.PSM.APSMA | HOCOMOCO | TAACGGt | 13.2 |
| OVOL2 (MA1545.2) | JASPAR | ACCGTTA | 11.9 |
| AC0278:OVOL:C2H2_ZF | Vierstra | ACCGTTA | 11.6 |
| AC0446:OVOL:C2H2_ZF | Vierstra | ACaGTTACa | 11.4 |
| AC0277:OVOL:C2H2_ZF | Vierstra | CCGtTA | 6 |
| M00234_2.00 | CIS-BP | CCGtTA | 5.9 |
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.