Motif Tools
Family atlas / CUT homeodomain

ONECUT (HNF6)

CUT homeodomainTATTGATTT18 motifsaka ONECUT, HNF6, HNF-6alpha
GACTATCTGATCT
representative: AC0624:ONECUT:CUT,Homeodomain · data consensus TATTGATT
members tight · 0.92stated TATTGATTT · data TATTGATT10 in vitro1 ChIP-only13 references, all PMIDs verified

ONECUT1 (HNF6), ONECUT2 and ONECUT3 bind DNA with a single CUT domain joined to a divergent homeodomain, and the two modules together read TATTGATT, often followed by a run of T. The same proteins also bind ATCGAT, the core preferred by the CUX proteins, and both forms appear across JASPAR, HOCOMOCO and CIS-BP. This is the most internally consistent family in the CUT class: cohesion is 0.92 and the three paralogues cannot be told apart from sequence. ONECUT1 is a liver, pancreas and biliary factor whose loss disrupts bile duct and endocrine pancreas development and causes human diabetes; ONECUT2 has become a target of interest in treatment-resistant and neuroendocrine prostate cancer.

The factors

Three human genes: ONECUT1 (HNF6, HNF-6alpha), ONECUT2 (OC-2) and ONECUT3 (OC-3). ONECUT1 was identified as a liver-enriched factor with an architecture no other homeodomain protein had at the time - a single CUT domain rather than the three CUT repeats of CUX1, followed by a homeodomain of a novel type 8790352. The ONECUT homeodomain differs from the canonical fold at positions that normally contact DNA, and it depends on the CUT domain for high-affinity binding, so the functional unit is bipartite 8790352,17223534. ONECUT1 is expressed in hepatocytes, biliary epithelium, pancreas and parts of the nervous system; ONECUT2 overlaps in liver and pancreas and is also expressed in retina and prostate; ONECUT3 is the least studied and is largely neural. The three are partly redundant, most clearly in retina, where Onecut1 and Onecut2 together, but neither alone, are required for early retinal cell fates 25228773.

The motif

The crystal structure of the bipartite DNA-binding domain of ONECUT1 bound to the HNF6 site of the transthyretin promoter shows the CUT domain and the homeodomain engaging adjacent stretches of the duplex, and the comparison with the DNA-free protein and with the OCT1 POU domain explains how the same protein can bind DNA in two distinct modes that use different coactivators 17223534. That structural duality shows up directly in the motif data. One set of models reads TATTGATT with a 3' T-rich extension - HOCOMOCO HNF6.H14CORE.0.PM.A gives TATTGATT, ONEC3.H14CORE.0.S.B gives TATtGATTT, and the JASPAR ONECUT1 and ONECUT3 models are the reverse complements AAATCAATA and AAAAATCAATAa. A second set reads ATCGAT, sometimes doubled: HNF6.H14CORE.2.S.B gives tATCGATcGAT, ONEC2.H14CORE.2.S.B gives TATCGATCG, and the JASPAR ONECUT2 model is GATCGATA. A ChIP-derived ONECUT2 model even resolves into six tandem ATTGAT repeats at 28 bits, which reflects clustered sites rather than a single long element. The pooled consensus is TATTGATT with cohesion 0.92, the highest in the CUT class. No position distinguishes ONECUT1, ONECUT2 and ONECUT3.

Where it acts

ONECUT1 sites sit in liver and pancreas promoters and enhancers. Promoter-array location analysis in human hepatocytes and pancreatic islets placed ONECUT1/HNF6 in one network with HNF1A and HNF4A: HNF1A and HNF4A occupy each other's promoters, and HNF6 heads feed-forward loops - for example binding the HNF4A P2 promoter and, with HNF4A, PCK1 - involving more than 80 genes in each tissue 14988562. The arrays covered only about 900 bp around each start site, so they show co-occupied promoters, not how close ONECUT, HNF1 and HNF4 sites lie to one another. In the developing pancreas, ONECUT1 acts upstream of NEUROG3 10825208. Because the informative core is about 8 bp and AT-rich, exact TATTGATT matches are expected on the order of 10^5 times in 3.1 Gb; the ATCGAT form is rarer, since CpG is depleted several-fold in the genome outside CpG islands. Tandem arrangements of ATTGAT, as in the archetype and ChIP-derived models, are a more distinctive signal than a single copy.

Biology and disease

Hnf6-null mice fail to form a normal biliary tract, with gallbladder agenesis and abnormal intrahepatic bile ducts 11934848, and show disrupted pancreatic endocrine differentiation through loss of Ngn3 expression 10825208. In humans, biallelic ONECUT1 mutations cause recessive syndromic diabetes with pancreatic hypoplasia and gallbladder agenesis or hypoplasia 34663987, confirmed as a cause of neonatal diabetes in a larger cohort 37639628. Heterozygous rare variants were proposed to define a dominant early-onset, non-autoimmune form 34663987, but that cohort found no enrichment of ONECUT1 variants among 484 unexplained MODY cases and associated only heterozygous null variants, not missense ones, with type 2 diabetes 37639628. ONECUT2 has emerged as a driver in prostate cancer: it suppresses the androgen receptor program and promotes neuroendocrine differentiation, and it is the target of active inhibitor development in castration-resistant and neuroendocrine disease 30478421,30655535. In retina, combined loss of Onecut1 and Onecut2 depletes horizontal cells and alters retinal ganglion cell production 25228773.

Reading a hit

A TATTGATT match, and especially a tandem ATTGATTGAT arrangement, is good evidence for a ONECUT factor, but it cannot say which of the three; the in vitro models are interchangeable. An ATCGAT-only match is genuinely ambiguous between ONECUT and CUX, and one Vierstra archetype is labelled CUX/ONECUT for exactly that reason 32728250 - resolve it with expression data, not with the motif. Evidence quality here is good: the HOCOMOCO A-grade models HNF6.H14CORE.0.PM.A and ONEC2.H14CORE.1.PM.A carry methyl-HT-SELEX (M) support, so the sequence claim does not rest on ChIP alone. Be cautious with the 28-bit tandem-repeat model, which will only match clustered sites and will miss ordinary single occurrences.

How this was worked out

  1. 1996mediumcDNA cloning, sequence analysis, promoter assays8790352

    HNF6 is cloned as the prototype of a sixth family of liver-enriched factors, with two DNA-binding domains: a single CUT domain and a homeodomain of a new type.

    Still open then: The sequence HNF6 reads, and how its two domains share it, were not yet defined.

  2. 2000mediumMouse gene targeting, promoter binding and reporter assays10825208

    Hnf6-null embryos have impaired pancreatic endocrine differentiation with Ngn3 expression almost abolished, HNF6 binds and stimulates the Ngn3 promoter, and adult mutants are diabetic.

  3. 2002mediumMouse gene targeting, histology, promoter assays11934848

    Hnf6-null mice lack a gallbladder and have abnormal extra- and intrahepatic bile ducts, with HNF1B downregulated, placing HNF6 upstream of HNF1B in biliary development.

  4. 2007highX-ray crystallography17223534

    The crystal structure of the HNF6 CUT domain plus homeodomain on the transthyretin promoter site, compared with the DNA-free protein and OCT1, shows how the bipartite domain engages DNA and gives a structural basis for two DNA-binding modes.

    Still open then: Which genomic sites use which binding mode was not mapped.

  5. 2014mediumMouse single and double knockouts, RNA-seq25228773

    Onecut1 and Onecut2 single knockouts reduce only horizontal cells, but the double knockout loses horizontal cells entirely and impairs cones, retinal ganglion cells and starburst amacrine cells, showing redundancy between the paralogues.

  6. 2018mediumNetwork analysis, functional genomics, xenografts, small-molecule inhibition30478421 30655535

    ONECUT2 is identified as a driver of castration-resistant and neuroendocrine prostate cancer that suppresses the androgen-receptor program and FOXA1, and a small-molecule inhibitor reduces metastasis in mice; a 2019 study independently links it to neuroendocrine plasticity through hypoxia signaling.

  7. 2021mediumHuman genetics, directed differentiation of pluripotent stem cells, chromatin profiling34663987

    Biallelic ONECUT1 mutations cause recessive syndromic diabetes with pancreatic hypoplasia and gallbladder agenesis, rare heterozygous variants are proposed to define an early-onset non-autoimmune subgroup, and loss of ONECUT1 in stem-cell-derived pancreatic progenitors impairs the endocrine program.

  8. 2023mediumSequencing of monogenic diabetes cohorts, rare-variant burden testing in >400,000 individuals37639628

    Large monogenic cohorts and UK Biobank confirm biallelic ONECUT1 variants as a cause of neonatal diabetes but find no enrichment of heterozygous variants in unexplained MODY; heterozygous null, not missense, variants associate with type 2 diabetes, revising the 2021 proposal of a MODY-like dominant form.

Still unresolved

How much to trust a hit

The three ONECUT paralogues share one motif, so a hit identifies the family only; use tissue expression to guess which one. ONECUT and CUX both prefer ATCGAT, and one Vierstra archetype is labelled CUX/ONECUT, so an ATCGAT-only match cannot be assigned between the two families. The TATTGATT core is short and AT-rich, giving roughly 10^5 expected chance matches genome-wide, so a single hit without footprint or expression support is weak. One ChIP-derived ONECUT2 model is a six-fold tandem repeat and behaves very differently from the single-site models - check which model produced your hit before interpreting its score.

References

18 motifs in this family — JASPAR 3 · HOCOMOCO 11 · CIS-BP 3 · Vierstra 1
motifdatabaseconsensusbits
ONEC2.H14CORE.3.P.BPBHOCOMOCOATTGATTgATTGATTgATTGAT28.3
HNF6.H14CORE.3.M.BMBHOCOMOCOtTATTGATTGAT19.2
HNF6.H14CORE.2.S.BSBHOCOMOCOtATCGATcGAT17.1
ONECUT3 (MA0757.2)JASPARAAAAATCAATAa16.7
ONEC2.H14CORE.2.S.BSBHOCOMOCOTATCGATCG16.1
ONEC3.H14CORE.2.M.CMCHOCOMOCOTATTGATTg15.8
ONEC2.H14CORE.1.PM.APMAHOCOMOCOTATTGATtg15.5
ONEC3.H14CORE.0.S.BSBHOCOMOCOTATtGATTT14.9
HNF6.H14CORE.1.S.BSBHOCOMOCOTATCGATt13.5
ONEC3.H14CORE.1.S.CSCHOCOMOCOATCGATT13.5
ONEC2.H14CORE.0.S.BSBHOCOMOCOTATCGATt13.4
ONECUT1 (MA0679.3)JASPARAAATCAATA13.3
M03715_2.00CIS-BPGATCGATA13.1
AC0624:ONECUT:CUT,HomeodomainVierstraTATTGATT13
ONECUT2 (MA0756.3)JASPARGATCGATA12.5
HNF6.H14CORE.0.PM.APMAHOCOMOCOTATTGATT12.3
M04677_2.00CIS-BPATCGATt11
M04667_2.00CIS-BPATCGATc9.5

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

ONECUTONECUT1ONECUT2ONECUT3
Find these in JASPAR →in HOCOMOCO →this entry as JSON →
how this page was made Drafted by a language model reading the primary literature, then checked: every cited PMID is resolved against PubMed and its citation text regenerated from PubMed's own record, and every claim about the motifs themselves is checked against the matrices in the four source databases. Methods and limits →

Other CUT homeodomain families

CUX (CUT homeodomain)
See this family on the motif map →Search your motif against the databases →