TALE homeodomain (PBX/MEIS/TGIF)
TALE homeodomain factors - PBX1-4, MEIS1-3, PKNOX1/2 (PREP1/2) and TGIF1/2 with the TGIF2LX/TGIF2LY retrogenes - carry a homeodomain with three extra residues inserted between helices 1 and 2, the Three Amino acid Loop Extension that names the class. That insertion creates a pocket that docks the hexapeptide of HOX proteins, which is how these factors turn otherwise generic HOX binding into specific composite sites. Two cores dominate the family: MEIS, PKNOX and TGIF read TGACAG, usually as the palindrome TGACAGCTGTCA, while PBX proteins read TGAT and assemble PBX-HOX elements (TGATTNAT) and PBX-MEIS elements (TGATTGACAG). These composite sites are the reason HOX and TALE factors have any DNA-level specificity at all.
The factors
The TALE superclass takes its name from a three-residue insertion between helices 1 and 2 of the homeodomain, recognized in 1997 in the MEIS, PBC, KNOX, Iroquois and TGIF groups 9336443. The human members here are the PBC class (PBX1-4), the MEIS class (MEIS1-3 and the more distantly related PKNOX1/PKNOX2, also called PREP1 and PREP2), and the TGIF class (TGIF1, TGIF2 and the X- and Y-linked retrogenes TGIF2LX and TGIF2LY). The Iroquois branch is treated separately in this atlas as HD_IRX. Beyond the homeodomain, PBX proteins carry PBC-A and PBC-B domains, and MEIS/PKNOX proteins carry the homologous MEIS/HR domains, through which the two groups heterodimerize with each other 9336443,16515781. PBX and MEIS/PKNOX are broadly expressed; TGIF1 and TGIF2 are widely expressed transcriptional repressors that also serve as Smad corepressors, linking the family to TGF-beta and NODAL signaling 10835638.
The motif
The extra three residues do two things. They lengthen the loop so that PBX can accommodate an additional fourth helix and, critically, they form part of a hydrophobic pocket that binds the hexapeptide (YPWM-like) motif found N-terminal to the homeodomain in most HOX proteins 7729685,10052460. A bare homeodomain reads only a 4-6 bp TAAT-type core, so HOX proteins on their own are nearly indistinguishable 22153072. Docking through the TALE pocket assembles a bipartite element: the HOXB1-PBX1 and HOXA9-PBX1 cocrystals show PBX occupying a TGAT half-site and the HOX partner an adjacent TNAT half-site, giving the composite TGATTNATNN, with the identity of the central bases set by the HOX paralogue 10052460,12923056,22153072. MEIS, PKNOX and TGIF read a different core, TGACAG 9343407, and in vitro they bind it overwhelmingly as the head-to-head palindrome TGACAGCTGTCA - the highest-information models in this family, up to 22 bits in JASPAR and CIS-BP, reported for TGIF1, TGIF2, PKNOX2, MEIS2 and MEIS3 alike 23332764. PBX-MEIS heterodimers instead give the asymmetric composite TGATTGACAG, seen in the ChIP-derived HOCOMOCO models for PBX1, PBX2, PBX3 and PKNOX1 23602564. Pooled, the family consensus is TGACAGCt with cohesion 0.74; the TGACAG and TGAT branches are readily distinguished from one another, but within each branch the paralogues are not.
Where it acts
PBX and MEIS/PKNOX sites are found in developmental enhancers, especially in and around the HOX clusters and in hindbrain and limb enhancers, where the composite elements confer the segment specificity that bare HOX motifs cannot 16515781. Genome-wide, PKNOX1/PREP1 and MEIS1 occupy largely independent site sets: PREP1 associates with promoters and housekeeping genes, MEIS1 with promoter-remote developmental regions, and HOX-type sequences co-occur with MEIS1 but not PREP1 binding sites, while PBX1 cooperates with both 23602564. Composite element names worth searching for are the PBX-HOX or hexapeptide element and the PBX-MEIS/PREP element. Because TGACAG is only 6 bp and TGAT only 4, matches to the half-sites are extremely common; an exact match to the 12-bp TGACAGCTGTCA palindrome, by contrast, is expected by chance only about 150-200 times in 3.1 Gb (3.1e9/4^12 is about 185).
Biology and disease
PBX1 loss in mouse disrupts skeletal patterning and chondrocyte differentiation 11566859, and PBX1 haploinsufficiency in humans causes syndromic congenital anomalies of the kidney and urinary tract 28270404. MEIS1 is the top locus in genome-wide association studies of restless legs syndrome 17637780. In cancer the family is best known for two mechanisms: the t(1;19) fusion E2A-PBX1 in pre-B acute lymphoblastic leukemia 1967983,1967982, and the collaboration of MEIS1 with HOXA9, where Hoxa9 transforms primary bone marrow cells specifically with Meis1a rather than Pbx1b 9649441 - a pairing that underlies MLL-rearranged leukemia. Heterozygous TGIF1 mutations cause holoprosencephaly, linking NODAL signaling to human neural axis determination 10835638.
Reading a hit
A TGACAGCTGTCA palindrome is strong evidence for a TALE factor but says nothing about which one: TGIF1, TGIF2, TGIF2LX, TGIF2LY, PKNOX1, PKNOX2, MEIS2 and MEIS3 all have essentially this model. A bare TGACAG or TGAT is too short to act on. The most useful reading is compositional: a TGATTNAT composite points to a PBX-HOX pair, and TGATTGACAG to a PBX-MEIS/PREP pair, and those are the hits worth following up. Note that several PBX and PKNOX models in HOCOMOCO are ChIP-only (P grade), so their TGATTGGC and TGATTGACAG variants may partly reflect the partner's contribution rather than PBX alone; one low-information CIS-BP entry in this family (CTAATTAa) has nearest neighbours in the K50 homeodomain group and is best ignored.
How this was worked out
PBX proteins, and the E2A-PBX1 oncoprotein, bind DNA cooperatively with a subset of HOX proteins, and the HOX hexapeptide (IYPWMK) upstream of the homeodomain is required; grafting it onto HOXA10 confers cooperativity.
Still open then: Where the hexapeptide docked on PBX was unknown.
A classification of all TALE homeobox genes, defined by three extra residues between helices 1 and 2, identifies PBC, MEIS, TGIF and IRO classes in animals and a MEIS domain related to the plant KNOX domain.
MEIS1 binds TGACAG and forms DNA-binding complexes with AbdB-like HOX proteins (paralogues 9-13) on a composite of a MEIS site and a TTTTACGAC HOX site; the HOX partner slows dissociation of MEIS1 from DNA.
The 2.35-A HOXB1-PBX1-DNA structure shows the HOXB1 hexapeptide bound in a pocket formed partly by the three-residue TALE insertion, and a fourth helix in PBX1 that stabilizes the complex.
The 1.9-A HOXA9-PBX1-DNA structure shows a posterior HOX hexapeptide in an altered conformation, and N-terminal arm residues that set specificity without contacting bases, explaining the different affinity and specificity of posterior HOX-PBX pairs.
SELEX-seq of all eight Drosophila HOX proteins with the Exd-Hth (PBX-MEIS) dimer reveals latent specificities absent from HOX monomers, falling into three classes that follow collinearity and differ in preferred minor-groove shape.
Still open then: How fully the classes map onto the human HOX-PBX pairs was not tested.
HT-SELEX of human factors gives the MEIS, PKNOX and TGIF proteins a head-to-head TGACAGCTGTCA palindrome of 18-22 bits, far more informative than the single TGACAG.
Still open then: Whether the palindrome is used in vivo was not addressed.
Genome-wide, PREP1 and MEIS1 occupy largely separate site sets with different sequences, PREP1 at promoters and housekeeping genes and MEIS1 at distal developmental elements with HOX-type sequences, revising the in vitro view that the two are interchangeable.
Still unresolved
- Whether the TGACAGCTGTCA palindrome is a common in vivo site is unresolved: HT-SELEX gives it for the MEIS, PKNOX and TGIF proteins, but every model in these databases that was built with ChIP data for the same factors gives a single TGACAG or a PBX composite instead.
- The ChIP-derived MEIS1 and MEIS2 models (JASPAR MA1639.2 and MA1640.2, HOCOMOCO MEIS1.H14CORE.0.P.B) read TGATTTAT, a PBX-HOX composite, rather than MEIS's own TGACAG, and how much MEIS occupancy in vivo is direct DNA binding versus recruitment through PBX-HOX complexes is not settled.
Within each branch the paralogues are interchangeable: the TGACAGCTGTCA palindrome is shared by TGIF1/2, TGIF2LX/2LY, PKNOX1/2 and MEIS1-3, and PBX1-4 share TGAT. Treat a hit as "TALE, MEIS/TGIF type" or "TALE, PBX type", not as a named protein. Half-site matches (TGACAG, TGAT) occur far too often to interpret. Several PBX and PKNOX models are ChIP-derived only (HOCOMOCO P grade) and their composite forms may carry a partner's half-site, which is informative but is not evidence that PBX alone binds it. One low-information CIS-BP member resolves to a K50 homeodomain site.
References
- Bürglin TR. Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. Nucleic Acids Res 1997;25:4173-80. PMID 9336443
- Chang CP, Shen WF, Rozenfeld S, et al. Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins. Genes Dev 1995;9:663-74. PMID 7729685
- Piper DE, Batchelor AH, Chang CP, et al. Structure of a HoxB1-Pbx1 heterodimer bound to DNA: role of the hexapeptide and a fourth homeodomain helix in complex formation. Cell 1999;96:587-97. PMID 10052460
- LaRonde-LeBlanc NA, Wolberger C. Structure of HoxA9 and Pbx1 bound to DNA: Hox hexapeptide and DNA recognition anterior to posterior. Genes Dev 2003;17:2060-72. PMID 12923056
- Shen WF, Montgomery JC, Rozenfeld S, et al. AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins. Mol Cell Biol 1997;17:6448-58. PMID 9343407
- Penkov D, Mateos San Martín D, Fernandez-Díaz LC, et al. Analysis of the DNA-binding profile and function of TALE homeoproteins reveals their specialization and specific interactions with Hox genes/proteins. Cell Rep 2013;3:1321-33. PMID 23602564
- Slattery M, Riley T, Liu P, et al. Cofactor binding evokes latent differences in DNA binding specificity between Hox proteins. Cell 2011;147:1270-82. PMID 22153072
- Moens CB, Selleri L. Hox cofactors in vertebrate development. Dev Biol 2006;291:193-206. PMID 16515781
- Selleri L, Depew MJ, Jacobs Y, et al. Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation. Development 2001;128:3543-57. PMID 11566859
- Le Tanno P, Breton J, Bidart M, et al. PBX1 haploinsufficiency leads to syndromic congenital anomalies of the kidney and urinary tract (CAKUT) in humans. J Med Genet 2017;54:502-510. PMID 28270404
- Kroon E, Krosl J, Thorsteinsdottir U, et al. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J 1998;17:3714-25. PMID 9649441
- Gripp KW, Wotton D, Edwards MC, et al. Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nat Genet 2000;25:205-8. PMID 10835638
- Jolma A, Yan J, Whitington T, et al. DNA-binding specificities of human transcription factors. Cell 2013;152:327-39. PMID 23332764
- Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 2007;39:1000-6. PMID 17637780
- Kamps MP, Murre C, Sun XH, et al. A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL. Cell 1990;60:547-55. PMID 1967983
- Nourse J, Mellentin JD, Galili N, et al. Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell 1990;60:535-45. PMID 1967982
62 motifs in this family — JASPAR 14 · HOCOMOCO 29 · CIS-BP 13 · Vierstra 6
| motif | database | consensus | bits |
|---|---|---|---|
| TGIF1 (MA0796.1) | JASPAR | TGACAGCTGTCA | 22.3 |
| M03223_2.00 | CIS-BP | TGACAGCTGTCA | 22.3 |
| M03178_2.00 | CIS-BP | TGACAGgTGTCA | 21.4 |
| PKNOX2 (MA0783.1) | JASPAR | TGACAGGTGTCA | 21.2 |
| M03195_2.00 | CIS-BP | TGACAGGTGTCA | 21.2 |
| M03171_2.00 | CIS-BP | TGACAGcTGTCA | 20.2 |
| TGIF2 (MA0797.1) | JASPAR | TGACAGcTGTCA | 18.4 |
| M03123_2.00 | CIS-BP | TGACAGcTGTCA | 18.4 |
| PKNX2.H14CORE.0.SM.BSMB | HOCOMOCO | TGACAGcTGTC | 16.4 |
| TF2LY.H14CORE.1.SM.BSMB | HOCOMOCO | TGACAGCTGTC | 16.4 |
| M02740_2.00 | CIS-BP | TGACAgCTGTC | 16.2 |
| MEIS2.H14CORE.2.SM.BSMB | HOCOMOCO | TTGACAGCTGtc | 16.1 |
| TGIF2.H14CORE.0.S.BSB | HOCOMOCO | TGACAGCTGTC | 16 |
| TF2LX.H14CORE.1.SM.BSMB | HOCOMOCO | TGACAGCTGtC | 15.8 |
| TGIF1.H14CORE.1.S.BSB | HOCOMOCO | TGACAGcTGTCA | 15.6 |
| MEIS3.H14CORE.1.S.BSB | HOCOMOCO | TGACAGCTGTcA | 15.3 |
| AC0086:MEIS/PKNOX:Homeodomain | Vierstra | TGACAGcTGTCA | 15.2 |
| PKNX1.H14CORE.3.SM.BSMB | HOCOMOCO | TGACAGgTGtc | 14.7 |
| M02685_2.00 | CIS-BP | TTGATTGAT | 14.6 |
| PBX1 (MA0070.2) | JASPAR | ATCAATCAA | 14.1 |
| TGIF2LX (MA1571.1) | JASPAR | TGACAGCTGTCA | 13.9 |
| PBX3 (MA1114.2) | JASPAR | TGAGTGACAGg | 13 |
| TF2LY.H14CORE.0.SM.BSMB | HOCOMOCO | TGACAGCt | 13 |
| M04951_2.00 | CIS-BP | TGACAgcTGTCA | 12.8 |
| TGIF2LY (MA1572.1) | JASPAR | TGACAgcTGTCA | 12.6 |
| M05313_2.00 | CIS-BP | TGACAgcTGTCA | 12.6 |
| PKNOX1 (MA0782.3) | JASPAR | TGAGTGACAG | 12.2 |
| PBX2 (MA1113.3) | JASPAR | CATAAATCA | 11.7 |
| MEIS1 (MA1639.2) | JASPAR | CATcAATCA | 11.7 |
| M08134_2.00 | CIS-BP | TGATTGACAg | 11.7 |
| PKNX2.H14CORE.1.SM.BSMB | HOCOMOCO | TGACAGgt | 11.6 |
| MEIS2 (MA1640.2) | JASPAR | TGATTTATG | 11.5 |
| PKNX1.H14CORE.1.P.BPB | HOCOMOCO | TGAtTGACAG | 11.5 |
| PKNX1.H14CORE.0.P.BPB | HOCOMOCO | TGATTGGC | 11.4 |
| AC0238:PBX/PKNOX:Homeodomain | Vierstra | TGAgTGACAG | 11.2 |
| MEIS2 (MA0774.1) | JASPAR | tTGACAGc | 11 |
| PBX3.H14CORE.0.P.BPB | HOCOMOCO | TGATTGGCnG | 11 |
| M00276_2.00looks like HD_Q50 | CIS-BP | CTAATTAa | 11 |
| MEIS1.H14CORE.0.P.BPB | HOCOMOCO | TGATTtATgg | 10.9 |
| PBX2.H14CORE.1.P.CPC | HOCOMOCO | TGATTGGC | 10.9 |
| TGIF2.H14CORE.1.PSM.APSMA | HOCOMOCO | TGACAG | 10.8 |
| MEIS2.H14CORE.1.PSM.APSMA | HOCOMOCO | TGACAGg | 10.6 |
| PBX1.H14CORE.0.P.BPB | HOCOMOCO | TGAtTGACaG | 10.6 |
| M07971_2.00 | CIS-BP | GCCAATca | 10.6 |
| MEIS3.H14CORE.0.SM.BSMB | HOCOMOCO | TGACA | 10.2 |
| AC0098:MEIS/PBX:Homeodomain | Vierstra | cATaAATCA | 10.2 |
| PBX3.H14CORE.1.P.BPB | HOCOMOCO | TGAtTGACaG | 9.9 |
| MEIS2.H14CORE.0.P.CPC | HOCOMOCO | TGATTtATg | 9.8 |
| PBX1.H14CORE.1.P.BPB | HOCOMOCO | TGATTGgC | 9.8 |
| PBX2.H14CORE.0.P.BPB | HOCOMOCO | TGAtTGACaG | 9.7 |
| PBX2.H14CORE.2.P.CPC | HOCOMOCO | AgTGACAG | 9.7 |
| AC0138:MEIS:Homeodomain | Vierstra | GGACAGgT | 9.3 |
| TF2LX.H14CORE.0.SM.BSMB | HOCOMOCO | TGACA | 9.1 |
| AC0096:PBX/HOXA:Homeodomain | Vierstra | TGATTGAT | 9 |
| MEIS3 (MA0775.2) | JASPAR | tTGACA | 8.9 |
| PBX1.H14CORE.2.P.BPB | HOCOMOCO | TGACAG | 8.9 |
| TGIF1.H14CORE.0.PSM.APSMA | HOCOMOCO | TGACAG | 8.6 |
| AC0087:MEIS/TGIF:Homeodomain | Vierstra | TGACAG | 8.6 |
| PKNX1.H14CORE.2.SM.BSMB | HOCOMOCO | TGACAg | 8 |
| M03165_2.00 | CIS-BP | TGACA | 7.9 |
| MEIS1 (MA0498.3) | JASPAR | TGACA | 7.8 |
| MEIS1.H14CORE.1.PS.APSA | HOCOMOCO | TGACAG | 7.5 |
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
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.