CENP-B / pogo / Tigger
The third and largest of the atlas's domesticated-transposase families. CENP-B, the Tigger-derived TIGD1 to TIGD7 proteins, POGK, JRK and CENPBD1 all carry DNA-binding domains descended from pogo, a Drosophila DNA transposon whose Tigger relatives left more than a hundred thousand fossil copies in the human genome. CENP-B itself recognizes the 17-base-pair CENP-B box, which recurs in alpha-satellite DNA - so a CENP-B box match is almost always centromeric or pericentromeric, not a regulatory site. Sixteen motifs cover twelve symbols, most of them sharing a bipartite pattern of a TTCG/CGAA block and a CCCG/CGGG block read by two helix-turn-helix domains. Cohesion is low at 0.48 and one model is flagged suspect.
The factors
In 1996 a survey of human interspersed repeats identified two roughly 2.5 kb elements with coding capacity, Tigger1 and Tigger2, that closely resemble pogo, a DNA transposon of Drosophila, and that probably mobilised at least fourteen families and more than a hundred thousand degenerate short copies carrying 14 to 25 base-pair terminal inverted repeats 8643651. The deduced pogo and Tigger transposases turned out to be very similar to CENP-B, the major mammalian centromere protein - the observation that first suggested CENP-B has a transposase origin 8643651. This family collects the human descendants of that lineage: CENPB itself, the Tigger transposable element derived proteins TIGD1 through TIGD7, POGK, JRK (jerky) and CENPBD1. TIGD7 was in fact isolated as a Jerky/JRK-like gene 15487591, and the wider pogo group also contains POGZ, which is not filed here.
Their host functions have diverged completely. CENP-B is a centromeric chromatin protein. Jerky, in Drosophila, facilitates cell-specific Wnt/Wingless signalling by modulating beta-catenin-TCF activity 21399610, and in mouse it is associated with translationally inactive neuronal mRNA. Several TIGD genes have no characterised function at all. What they retain in common is the recognition module, which is exactly what makes this family readable as a motif family and unreadable as a functional one.
The motif
CENP-B binds a 17 base-pair sequence in centromeric alpha-satellite (alphoid) DNA, purified from HeLa nuclear extract as the protein that recognizes it, with an affinity of about 6 x 10^8 M^-1, and the major protein-DNA complex contains two DNA molecules 1730770. The 129-residue DNA-binding region forms two helix-turn-helix domains that occupy adjacent major grooves; the DNA is kinked at both recognition-helix contacts, the larger kink reaching 43 degrees through an arginine-rich helix that bridges the phosphate backbone, giving an overall bend of 59 degrees 11726497. The box recurs in alpha-satellite at regular intervals, roughly every other repeat unit 11726497,17115329.
The atlas models for CENPB, tCCCGCaTnntACGAA in HOCOMOCO and CCCGcdTnnwaCGAA in CIS-BP and Vierstra, are written on the strand opposite the way the box is conventionally quoted: the CCCG block at their 5' end corresponds to the CGGG block at the 3' end of the box, and their 3' CGAA corresponds to the box's 5' TTCG. Read in either orientation the bipartite architecture is visible, two conserved blocks separated by a tolerant spacer, exactly matching the two-helix-turn-helix structure. The same signature runs through the family: JRK gives CCTCgrTTAACCGGAA, TIGD7 ttCnnTAATTCGGAC, TIGD4 ACCCCGTTAaTAcGAaC, TIGD3 TATGCAGgTAAcCGda, TIGD5 cccbtTATAACGC and POGK TCGACcTtAgGTCGACa. These are long, information-rich models of 12 to 26 bits with grade A HOCOMOCO evidence 42557334, but they are not the same site as each other, which is why family cohesion is only 0.48. The tail is weak: TIGD1 gives TATTGCG, CENPBD1 TACGta at 4.1 bits, TIGD6 aaCGAA at 3.4 bits, and the Vierstra archetype AC0265 collapses to CG and is flagged suspect with SAND as its alternative family. Two CIS-BP models, for TIGD2 and TIGD6, are transferred from Monodelphis domestica, and a third for POGK is a PBM construct at only 73 percent domain identity.
Where it acts
For CENP-B the answer is unusually definite: its sites are in alpha-satellite arrays at centromeres and pericentromeric regions, distributed through higher-order repeat units 17115329, and they are functional there. Both the CENP-B box and alphoid sequence context are required for de novo centromere chromatin assembly on synthetic repeats in the human artificial chromosome assay, including recruitment of CENP-A, CENP-C and CENP-E 12460987; combining CENP-B box positive and negative synthetic repeats improves artificial chromosome formation further 35563684. Alpha-satellite arrays differ in their CENP-B box content 17115329, and the box has arisen independently more than once - it is present in some New World monkey satellite lineages with separate origins 31813924. The other members are nuclear proteins of unremarkable distribution whose genomic occupancy is poorly mapped.
Biology and disease
The centromeric role of the box is not matched by a requirement for the protein: Cenpb null mice are viable with no apparent abnormalities 9740654, so CENP-B is best understood as facilitating centromere assembly rather than being essential to it. This is the standard picture for domesticated transposases, whose retention reflects opportunistic recruitment rather than indispensability. Jerky loss in mouse produces an epilepsy phenotype 7550318, and the fly orthologue modulates Wnt signalling through beta-catenin-TCF 21399610. The Tigger and POGK members remain largely uncharacterised; POGZ, a pogo relative outside this family, is a well-established neurodevelopmental disorder gene, which is a reason to expect more phenotypes here.
Reading a hit
Check repeat annotation first. A CENP-B box match will nearly always fall inside alpha satellite, and in that context it is a structural feature of the centromere, not a candidate enhancer; counting matches is effectively counting satellite repeat units, and satellite arrays are poorly resolved in most reference assemblies, so occurrence counts are unreliable. For the rest of the family, the long grade A models for JRK, POGK, TIGD3, TIGD4, TIGD5 and TIGD7 are individually specific and mutually distinct, so a hit can be assigned to a member rather than only to the family - but almost nothing is known about what those sites do, and there is no occupancy evidence to corroborate them. Discard the CENPBD1, TIGD6 and TIGD1 models, the cross-species transfers, and the suspect CG archetype.
How this was worked out
- 1992highOligonucleotide affinity purification, EMSA, Southwestern blotting, DNase I footprinting1730770
CENP-B was purified from HeLa nuclear extract as the protein that binds the 17 bp CENP-B box of alpha-satellite DNA, with direct binding shown by mobility shift, Southwestern blotting and DNase I protection, a binding constant of about 6 x 10^8 M^-1, and a major complex containing two DNA molecules.
Still open then: Whether CENP-B is needed for centromere function.
An insertional mutation in mice inactivated jerky, a novel gene related to CENP-B, and caused whole-body jerks, generalized clonic seizures and epileptic brain activity.
Still open then: Whether the jerky protein binds DNA, and at which sites.
Tigger1 and Tigger2, 2.5 kb human DNA transposon fossils resembling Drosophila pogo, were identified along with more than 100,000 degenerate short copies; their deduced transposases were very similar to CENP-B, implying that CENP-B is a domesticated transposase.
Cenpb null mice were viable and fertile with normal mitosis and meiosis, contradicting the proposal that CENP-B performs a vital role in organizing centromeric chromatin.
Still open then: What the conserved CENP-B box does if the protein that binds it is dispensable.
The crystal structure of the 129-residue CENP-B DNA-binding region on the CENP-B box showed two helix-turn-helix domains in adjacent major grooves, a kink-straight-kink DNA path with a 43 degree kink made by phosphate bridging from an arginine-rich helix, and an overall bend of 59 degrees.
Synthetic repeats with mutated CENP-B boxes failed to form mammalian artificial chromosomes or assemble CENP-A, CENP-C and CENP-E, showing that the box and alphoid sequence are both required for de novo centromere assembly in human cells despite the viability of Cenpb null mice.
Still open then: Why a box required for de novo assembly is dispensable in the whole animal.
Phylogenetic analysis of centromere satellite repeats in three New World monkeys placed the CENP-B box at a different location in each species, supporting multiple independent origins of the box rather than inheritance from a common ancestor.
A multi-assay survey of poorly characterized human transcription factors found that CENP-B- and Brinker-domain proteins give long, information-rich motifs, and that JRK binding in both ChIP-seq and GHT-SELEX is enriched on the Tigger15a elements it derives from, with predicted sites in their terminal repeats; this supplied occupancy data for a family member other than CENP-B.
Still open then: Whether the TIGD and POGK sites likewise mark their ancestral transposon fossils.
Still unresolved
- Why the CENP-B box is required for de novo centromere assembly on synthetic alphoid DNA while Cenpb null mice are viable and fertile is unresolved; current work places CENP-B in the balance between CENP-A chromatin and heterochromatin rather than as an essential centromere component, but whether it matters only for establishment is not settled.
- Whether the long motifs of JRK, POGK and the TIGD proteins describe host regulatory sites or remnants of ancestral transposon recognition is open: JRK binding is enriched on the Tigger15a elements it descends from, with predicted sites in their terminal repeats, but what that binding does for the host has not been shown.
- It is not known whether JRK's DNA specificity bears on its reported cellular roles, since the fly orthologue acts as a beta-catenin-TCF coactivator and mouse Jerky has been described in association with neuronal mRNA, neither of which has been tied to the motif.
This is a low-cohesion family (0.48) whose members do not share one site: only CENPB, and the models labelled CENPB, correspond to the CENP-B box, and those are written reverse-complement to the usual rendering of the box. A CENP-B box hit is almost always inside alpha satellite and should be read as centromeric structure, not regulation; match counts there track satellite copy number and assembly quality rather than biology. Four models are effectively uninformative (CENPBD1 4.1 bits, TIGD6 3.4 bits, the suspect CG archetype AC0265, and TIGD1's seven-base TATTGCG). Two CIS-BP models are transferred from Monodelphis domestica and one POGK model from a PBM construct at 73 percent domain identity. No member except CENPB has published occupancy data to corroborate its motif.
References
- Smit AF, Riggs AD. Tiggers and DNA transposon fossils in the human genome. Proc Natl Acad Sci U S A 1996;93:1443-8. PMID 8643651
- Muro Y, Masumoto H, Yoda K, et al. Centromere protein B assembles human centromeric alpha-satellite DNA at the 17-bp sequence, CENP-B box. J Cell Biol 1992;116:585-96. PMID 1730770
- Tanaka Y, Nureki O, Kurumizaka H, et al. Crystal structure of the CENP-B protein-DNA complex: the DNA-binding domains of CENP-B induce kinks in the CENP-B box DNA. EMBO J 2001;20:6612-8. PMID 11726497
- Ohzeki J, Nakano M, Okada T, et al. CENP-B box is required for de novo centromere chromatin assembly on human alphoid DNA. J Cell Biol 2002;159:765-75. PMID 12460987
- Perez-Castro AV, Shamanski FL, Meneses JJ, et al. Centromeric protein B null mice are viable with no apparent abnormalities. Dev Biol 1998;201:135-43. PMID 9740654
- Okazaki K, Nakano M, Ohzeki JI, et al. Combination of CENP-B Box Positive and Negative Synthetic Alpha Satellite Repeats Improves De Novo Human Artificial Chromosome Formation. Cells 2022;11. PMID 35563684
- Thongchum R, Nishihara H, Srikulnath K, et al. The CENP-B box, a nucleotide motif involved in centromere formation, has multiple origins in New World monkeys. Genes Genet Syst 2020;94:301-306. PMID 31813924
- Rosandić M, Paar V, Basar I, et al. CENP-B box and pJalpha sequence distribution in human alpha satellite higher-order repeats (HOR). Chromosome Res 2006;14:735-53. PMID 17115329
- Dou T, Gu S, Zhou Z, et al. Isolation and characterization of a Jerky and JRK/JH8 like gene, tigger transposable element derived 7, TIGD7. Biochem Genet 2004;42:279-85. PMID 15487591
- Benchabane H, Xin N, Tian A, et al. Jerky/Earthbound facilitates cell-specific Wnt/Wingless signalling by modulating β-catenin-TCF activity. EMBO J 2011;30:1444-58. PMID 21399610
- Sinzelle L, Izsvák Z, Ivics Z. Molecular domestication of transposable elements: from detrimental parasites to useful host genes. Cell Mol Life Sci 2009;66:1073-93. PMID 19132291
- Jangam D, Feschotte C, Betrán E. Transposable Element Domestication As an Adaptation to Evolutionary Conflicts. Trends Genet 2017;33:817-831. PMID 28844698
- Toth M, Grimsby J, Buzsaki G, et al. Epileptic seizures caused by inactivation of a novel gene, jerky, related to centromere binding protein-B in transgenic mice. Nat Genet 1995;11:71-5. PMID 7550318
- Jolma A, Laverty KU, Fathi A, et al. An expanded codebook of human transcription factor DNA-binding specificity. Nature 2026;657:275-283. PMID 42557334
16 motifs in this family — HOCOMOCO 7 · CIS-BP 6 · Vierstra 3
| motif | database | consensus | bits |
|---|---|---|---|
| JERKY.H14CORE.0.PSGB.APSGBA | HOCOMOCO | CCTCgrTTAACCGGAA | 25.9 |
| POGK.H14CORE.0.SI.ASIA | HOCOMOCO | TCGACcTtAgGTCGACa | 21.7 |
| TIGD3.H14CORE.0.PSGIB.APSGIBA | HOCOMOCO | TATGCAGgTAAcCGda | 21.3 |
| TIGD4.H14CORE.0.SGI.ASGIA | HOCOMOCO | ACCCCGTTAaTAcGAaC | 20.7 |
| CENPB.H14CORE.0.S.BSB | HOCOMOCO | tCCCGCaTnntACGAA | 16.9 |
| TIGD7.H14CORE.0.SGIB.ASGIBA | HOCOMOCO | ttCnnTAATTCGGAC | 15.2 |
| M02939_2.00 | CIS-BP | CCCGcdTnnwaCGAA | 14 |
| AC0551:CENPB:CENPB | Vierstra | CCCGcdTnnwaCGAA | 14 |
| M01131_2.00PBM CONSTRUCTS 0.73 | CIS-BP | aAAGCCGA | 13.4 |
| TIGD5.H14CORE.0.PSGI.APSGIA | HOCOMOCO | cccbtTATAACGC | 12.2 |
| M01204_2.00 | CIS-BP | TATTGCG | 9.7 |
| AC0449:TIGD:CENPB | Vierstra | TATTGCG | 9.3 |
| M01206_2.00Monodelphis domestica 0.94 | CIS-BP | gCGGaT | 5 |
| M01203_2.00 | CIS-BP | TACGta | 4.1 |
| M01205_2.00Monodelphis domestica 0.96 | CIS-BP | aaCGAA | 3.4 |
| AC0265:CENPBD/GMEB:CxxClooks like SAND | Vierstra | CG | 3.2 |
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.