Bioinformatics Advance Access originally published online on October 10, 2006
Bioinformatics 2006 22(23):2841-2845; doi:10.1093/bioinformatics/btl498
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Meisetz and the birth of the KRAB motif
Department of Physiology, Anatomy and Genetics, MRC Functional Genetics Unit, University of Oxford South Parks Road, Oxford OX1 3QX, UK
*To whom correspondence should be addressed.
 |
ABSTRACT |
|---|
 TOP ABSTRACT 1 INTRODUCTION2 RESULTS AND DISCUSSION3 CONCLUSIONSREFERENCES |
|---|
The largest family of transcription factors in mammals is of Cys2His2 zinc finger-proteins, each with an NH2-terminal KRAB motif. Extensive expansions of this family have occurred in separate mammalian lineages, with 
400 such genes known in the human genome. Despite their widespread occurrence, the evolutionary provenance of the KRAB motif is unclear since previously it has not been found outside of the tetrapod vertebrates. Here, we show that homologues of the histone methyltransferase Meisetz are present within the sea urchin (Strongylocentrotus purpuratus) genome. Sea urchin and mammalian Meisetz sequences each contain an N-terminal KRAB motif, which thereby establishes an early origin of the KRAB motif prior to the divergence of echinoderm and chordate lineages. Finally, we present evidence that KRAB motifs derive from a novel family of KRI (KRAB Interior) motifs that were present in the last common ancestor of animals, plants and fungi.
Contact: chris.ponting{at}anat.ox.ac.uk
Supplementary information: Supplementary data for this article are available at Bioinformatics online.
|
1 INTRODUCTION |
|---|
|
TOPABSTRACT1 INTRODUCTION2 RESULTS AND DISCUSSION3 CONCLUSIONSREFERENCES |
|---|
Krüppel-associated box (KRAB) motif—and krüppel Cys2His2 zinc finger-encoding transcription factors present three enduring mysteries. The first of these is the molecular basis to their unprecedented family expansions in mammalian genomes. KRAB motifs are encoded in
either 300–400 genes in the human or mouse genomes (Huntley et al., 2006). Many of these arose either in the human or in the mouse lineage by gene duplication in the last 80 million years, with dispersal to many distinct chromosomes [(Faisst and Meyer, 1992; Rousseau-Merck et al., 2002; Urrutia, 2003; Huntley et al., 2006) and references therein]. As the vast majority of these genes are of unknown function, it is unclear what selective processes governed these gene family expansions. The second mystery is the rapid evolution of mammalian KRAB motifs. Among all known families of domains or motifs, KRAB motifs appear, on average, to have evolved the fastest (Waterston et al., 2002). Currently, it is unknown whether such divergent evolution results from reductions in selective constraints or from adaptive evolution.
The final mystery is the evolutionary provenance of the KRAB motif itself. Despite the large numbers of this motif encoded in mammalian genomes (Bellefroid et al., 1991; Huntley et al., 2006), strangely it has only been found in proteins from tetrapod vertebrates (Looman et al., 2002; Urrutia, 2003). KRAB motifs appear to be absent from more divergent vertebrates, such as fish, from non-vertebrate eukaryotes and from prokaryotes (Lander et al., 2001). Extant domain families, such as that of KRAB, are not thought to have emerged recently from non-coding DNA (Ponting et al., 2002). Rather, it is predicted that essentially all protein families arose from duplication of pre-existing coding sequence, which often diverges sufficiently rapidly to render imperceptible residual similarities in sequence (Copley et al., 2003).
Within KRAB-Cys2His2 transcription factors, KRAB motifs are thought to mediate protein–protein interactions (Bellefroid et al., 1991; Urrutia, 2003) whereas the Cys2His2 zinc fingers bind the major groove of B-DNA by packing their single 
-helices against 3 bp subsites (Pavletich and Pabo, 1991). Typically, these factors' KRAB motifs are divisible into two. All KRAB-containing genes contain the KRAB A motif, which appears often to mediate a transcription repression function (Margolin et al., 1994). KRAB A may occur alone, but commonly it is accompanied by an additional KRAB B modulatory motif (Huntley et al., 2006). KRAB A and B motifs are each encoded by separate exons and these are invariably positioned N-terminal to tandem arrays of Cys2His2 zinc fingers, often all encoded within a single exon (Miller et al., 1985; Shannon et al., 1998). The exception to this KRAB-Cys2His2 zinc finger domain architecture is the family of SSX (Synovial sarcoma, X breakpoint) proteins, which possess an N-terminal and sequence-divergent KRAB motif unaccompanied by zinc fingers (Lim et al., 1998).
Recently, a putative transcription factor gene named Meisetz was characterized, which appears to possess a role in the progression of early meiotic prophase. Meisetz–/– mice are sterile and exhibit deficits in meiosis (Hayashi et al., 2005). The Meisetz protein contains both a central SET (Suvar3–9, Enhancer-of-zeste, Trithorax) domain, which catalyses the trimethylation of lysine 4 in histone H3, and a C-terminal array of tandem Cys2His2 zinc fingers all encoded in a single exon.
Our interest in Meisetz arose initially from an observation that it contains a hitherto unrecognized N-terminal KRAB motif, similar to those of SSX proteins. Subsequently, we realized that Meisetz is not specific to mammals since the purple sea urchin (Strongylocentrotus purpuratus) possesses Meisetz orthologues. Furthermore, single N-terminal KRAB domains are apparent within these sequences, and similar homologues from amphioxus (Branchiostoma floridae), and from sea squirts (Ciona intestinalis and Ciona savignyi). This pushes back the origins of this enigmatic domain to at least the common deuterostome ancestor of vertebrates and echinoderms. Eventually, by exploiting the divergence of these early-branching KRAB motifs, we obtained evidence for the common ancestry of the KRAB A motif with a novel KRI (KRAB Interior) motif present in molecules from among the crown group of eukaryotes, the fungi, plants and animals. KRI occurs within proteins possessing chromatin-related functions, and also alongside other domains predicted to be involved in transcriptional regulation. The cellular function of KRAB may thus have been inherited from its pre-existing KRI ancestor.
|
2 RESULTS AND DISCUSSION |
|---|
|
TOPABSTRACT1 INTRODUCTION2 RESULTS AND DISCUSSION3 CONCLUSIONSREFERENCES |
|---|
2.1 Meisetz contains an N-terminal KRAB motif
Mouse (Mus musculus) Meisetz, and its mammalian orthologues, were each found to possess an N-terminal KRAB motif. Searches of the SMART database (Ponting et al., 1999) and the conserved domain database (Marchler-Bauer and Bryant, 2004) revealed significant similarities (E = 5.5 x 10–8 and 1 x 10–9, respectively) to known KRAB motifs. In addition, using a hidden Markov model of the putative KRAB motif from seven vertebrate and non-vertebrate chordates (see below), Meisetz KRAB motifs were found to be substantially more similar to those in mammalian SSX proteins (7 x 10–17 < E < 4.5 x 10–3) than those in KRAB-Cys2His2 zinc finger proteins (E > 0.14), in a search of all known protein sequences (Fig. 1).
|
2.2 MEISETZ homologues outside of mammals
Unexpectedly, we found evidence for Meisetz homologues in three diverse non-vertebrate chordates (Delsuc et al., 2006), an echinoderm, a cephalochordate and a tunicate. Each of these homologues contains a single N-terminal KRAB motif, which represent the first recorded members of this family from outside of tetrapod vertebrates.
First, by comparing mouse Meisetz with current protein sequences using BLASTP (Altschul et al., 1997), we identified a Meisetz homologue (XP_799022 [GenBank] .1; E = 7 x 10–47) from an echinoderm, the California purple sea urchin (S.purpuratus). Indeed, further investigation of the draft sea urchin genome revealed a total of three complete, and also three incomplete, sequence-similar Meisetz homologues. Given the increased levels of heterozygosity of the sea urchin genome sequenced, some of the multiple Meisetz homologues in the assembly may instead represent allelic variants. A Meisetz-like KRAB motif was then found in expressed sequence tags (ESTs) from amphioxus (B.floridae, GenBank accession nos BW709598 [GenBank] and BW709302 [GenBank] ). Finally, a divergent Meisetz homologue was also apparent in the genome assembly of a tunicate, C.intestinalis, whose predicted amino acid sequence is significantly similar to a human Meisetz orthologue, PRDM9 (E = 7 x 10–8), including within its KRAB motif.
Next, using BLASTP (Altschul et al., 1997), we detected a Meisetz-like gene encoding SET and 14 C-terminal Cys2His2 zinc fingers in zebrafish (Danio rerio; RefSeq NP_957196 [GenBank] .1). This gene's orthologues in two pufferfish (Tetraodon nigroviridis and Takifugu rubripes) genomes, and in ESTs from the minnow (Pimephales promela), were then also identified using BLAT (Kent 2002) and TBLASTn, respectively. A KRAB motif was apparent neither from the zebrafish cDNA, nor from three minnow ESTs in their short regions up to the 5'-most in-frame stop codon, nor from orthologous pufferfish gene predictions, and nor from upstream genomic sequence.
Phylogenetic analysis of these sequences' SET domains (Supplementary Fig. 1) indicates that the mammalian, fish and sea urchin Meisetz genes are orthologous, whereas the sea squirt homologues may have acquired the KRAB-SET-Cys2His2 zinc fingers' domain architecture of Meisetz independently. We were unable to identify Meisetz homologues in the chicken (Gallus gallus) or frog (Xenopus tropicalis) genomes, which are the only genomes from outside the mammals previously known to encode KRAB motifs.
The S.purpuratus Meisetz homologues possess domain architectures equivalent to those of mammals and thus they each possess a KRAB motif. For example, using HMMER (Eddy 1998) we find that a sea urchin Meisetz sequence (XP_799022 [GenBank] .1) is significantly similar (E = 8 x 10–3) to an alignment of known KRAB motif sequences (Marchler-Bauer and Bryant, 2004). S.purpuratus, C.intestinalis and mammalian Meisetz genes were also found to share equivalent exon boundaries about their KRAB motifs.
We conclude that Meisetz originated prior to the last common deuterostome ancestor of chordates and echinoderms at least 520 million years ago (MYA) (Blair and Hedges, 2005). Moreover, as sea urchin Meisetz genes encode KRAB motifs we have pushed back the origins of KRAB motifs from 370 MYA (the last common ancestor of frogs and mammals (Blair and Hedges, 2005)) by >140 MY. As no other, more distantly-related, KRAB motifs are recognizable, using exhaustive BLAST (Altschul et al., 1997) and HMMER (Eddy, 1998) searches, within current invertebrate (including sea urchin) protein sequences, the Meisetz KRAB motif is thus a good candidate for being the progenitor motif from which all other KRAB family members were derived.
The antiquity of the KRAB motif is consistent with the phyletic distribution of KAP1 (also called Krip-1 or TIF1ß) orthologues (Friedman et al., 1996), to which, in mammalian proteins, it binds [with the notable exception of these motifs in SSX proteins (Lim et al., 1998)]. However, despite the apparent absence of KRAB motifs in arthropods, a single orthologue of the three TIF1/TIF1ß/TIF1
molecules is found in the fruitfly, where, as in mammals, it possesses a role in chromatin-mediated transcriptional repression (Beckstead et al., 2001).
2.3 KRI—a KRAB progenitor
Our unexpected observation of KRAB motifs in invertebrate chordate proteins prompted an investigation seeking to identify KRAB motif homologues from earlier-branching, non-metazoan eukaryotes, such as plants and fungi. Indeed, significant sequence similarity (E = 2 x 10–4, fourth iteration) was detected between the N-terminal region of Saccharomyces cerevisiae YDL156W, a nuclear protein (Huh et al., 2003), and the KRAB motif region of sea urchin Meisetz. This search used PSI-BLAST (Altschul et al., 1997) and an E-value inclusion threshold of E < 2 x 10–3 in a comparison of the first 180 amino acids of the S.cerevisiae protein with the NCBI's non-redundant protein sequence database (nr). This search was suggested because of an initial, albeit non-significant, similarity found between the Saccharomyces kluyveri YDL156W gene (contig AACE02000536.1; 725–973 nt) and the N-terminal 1–183 amino acids of sea urchin Meisetz (TBlastN search: 38.5 bits; E = 0.47).
Furthermore, 25 additional putative homologues (E < 0.1) of this motif were collated in three iterations of database searches using a hidden Markov model constructed (Eddy, 1998) from a multiple alignment of 13 fungal YDL156W orthologues. A further 10 putative homologues were then identified by searching nr with S.cerevisiae YDL156W (1–90 amino acids) using PSI-BLAST in ungapped mode (options -G 32767 -E 32767 -h 0.005) in 13 iterations. The extent of the motif was defined on the basis that it encompassed the most N- and C-terminal amino acids of Yarrowia lipolytica YDL156W and Cryptococcus neoformans CNBA3050 (GenInfo identifiers [gi] 50556624 and 50261008), respectively.
These sequences were then found to be significantly similar to KRAB motifs using two methods that compare amino acid alignments. When an alignment of these 35 YDL156W-like motifs was compared with an alignment of 8 KRAB motifs from Meisetz- and SSX-like proteins using COMPASS (Sadreyev and Grishin, 2003), a highly significant E-value of 2.9 x 10–10 was obtained. Similarly, comparison of YDL156W-like and Meisetz-like KRAB motif alignments, using LAMA (Pietrokovski, 1996) generated a highly significant Z-score of 10.1. In a random simulation involving 7 million block pair comparisons no alignments yielded Z-scores >8.3 (Pietrokovski, 1996); hence, the expected number of random block alignments with a Z-score by chance equal to, or greater than, 10.1 is essentially zero.
These significant sequence similarities between short regions of fungal YDL156W and animal Meisetz proteins (Fig. 1) indicate that they evolved convergently, or they are homologous, they share a common ancestor. Convergence appears less likely given the strong sequence similarities between these two motifs, their common phylogenetic distributions and the functional similarities between their co-occurring domains (see below). Assuming homology, we term the YDL156W, and similar, sequences KRI or KRAB Interior motifs since they align against the interior of Meisetz KRAB motifs. KRI motifs match the known -helical regions of KRAB motifs (Fig. 1).
KRI motifs are present in proteins from all major eukaryote lineages, including plants Arabidopsis thaliana and Oryza sativa (rice), and ascomycete fungi Neurospora crassa and Aspergillus nidulans (in addition to the Saccharomyces species described above). Despite Meisetz KRAB motifs being apparently absent in fish and frogs, we find KRI homologues in fish (e.g. T.nigroviridis sequence gi:472218092) and frog species (e.g. Xenopus laevis sequence gi:68533974) and otherwise throughout the vertebrates.
The wider phyletic distribution of KRI, compared to KRAB, motifs suggests that the 26 amino acid KRI sequence may be the progenitor of KRAB. In this model, accretion of additional sequence to KRI formed the KRAB A sequence in an early deuterostome Meisetz protein. This KRAB A motif, we predict, represents the founder member of all extant mammalian KRAB A motifs.
2.4 KRI motif function
In the main, the functions of KRI motifs remain obscure. However, in the Myc-interacting protein JPO2 (also known as R1, RAM2 or CDCA7L) the KRI motif is known, from experiments involving short 6 amino acid deletions within the motif, to be important for binding to the DNA transcription factor, c-Myc (Huang et al., 2005). Other studies suggest that JPO2 localizes to chromatin (Maertens et al., 2006), and possesses transcriptional repressor activity (Chen et al., 2005). A chromatin-related function for KRI motifs also suggested from consideration of the architectures of the proteins in which they occur (Fig. 2). KRI motif proteins contain, in addition, at least six other domain types. Of these, members of the CHROMO and WD40 domain families are known to bind lysine-methylated histones (Bannister et al., 2001; Wysocka et al., 2005); UIM domains bind ubiquitin, and methylation of lysine 4 histone H3 requires ubiquitylation of histone H2B (Sun and Allis, 2002) and RING finger proteins are E3 ubiquitin ligases, some of which promote ubiquitylation of histones H2A and H2B in vitro (Minsky and Oren, 2004). Just as a KRAB motif typically co-opts other proteins into DNA-associated protein complexes, so might a KRI motif, perhaps via its single predicted -helix that it shares in common with KRAB motifs.
|
|
3 CONCLUSIONS |
|---|
|
TOPABSTRACT1 INTRODUCTION2 RESULTS AND DISCUSSION3 CONCLUSIONSREFERENCES |
|---|
Most KRAB domain proteins co-localize with the lysine 9 histone H3 methyltransferase SETDB1 via KAP1 and thus assist in transcriptional repression (Schultz et al., 2002). By way of contrast, Meisetz is a lysine 4 histone H3 methyltransferase that appears to be a transcriptional activator of genes that are critical for the progression of meiotic prophase (Hayashi et al., 2005). It is thus plausible that the progenitor Meisetz KRAB was involved in transcriptional activation but that this function was subverted by later evolving proteins which exploited the motif for transcription repression purposes.
In summary, we have identified a new family of KRI motifs from which, prior to the split of echinoderms and chordates, the Meisetz KRAB motif arose. This KRAB motif may represent the founder member for the hundreds of KRAB motifs encoded in multiple mammalian genomes. The functions of KRI and Meisetz KRAB motifs will need to be experimentally determined if we are to better appreciate the function and evolution of these important transcriptional regulators.
|
Acknowledgments |
|---|
The authors thank the Ponting group, in particular Leo Goodstadt, for helpful discussions and advice. This work was funded by the UK Medical Research Council (MRC). Funding to pay the Open Access publication charges for this article was provided by the MRC.
Conflict of Interest: none declared.
|
FOOTNOTES |
|---|
Associate Editor: Alex Bateman
Received on August 8, 2006; revised on September 26, 2006; accepted on September 27, 2006
|
REFERENCES |
|---|
|
TOPABSTRACT1 INTRODUCTION2 RESULTS AND DISCUSSION3 CONCLUSIONSREFERENCES |
|---|
Altschul, S.F., et al. (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res, . 25, 3389–3402
Bannister, A.J., et al. (2001) Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature, 410, 120–124[CrossRef][Medline].
Beckstead, R., et al. (2001) Bonus, a Drosophila homolog of TIF1 proteins, interacts with nuclear receptors and can inhibit betaFTZ-F1-dependent transcription. Mol. Cell, 7, 753–765[CrossRef][Web of Science][Medline].
Bellefroid, E.J., et al. (1991) The evolutionarily conserved Kruppel-associated box domain defines a subfamily of eukaryotic multifingered proteins. Proc. Natl Acad. Sci. USA, 88, 3608–3612
Berman, H.M., et al. (2000) The Protein Data Bank. Nucleic Acids Res, . 28, 235–242
Blair, J.E. and Hedges, S.B. (2005) Molecular phylogeny and divergence times of deuterostome animals. Mol. Biol. Evol, . 22, 2275–2284
Chen, K., et al. (2005) R1, a novel repressor of the human monoamine oxidase A. J. Biol. Chem, . 280, 11552–11559
Copley, R.R., et al. (2003) Eukaryotic domain evolution inferred from genome comparisons. Curr. Opin. Genet. Dev, . 13, 623–628[CrossRef][Web of Science][Medline].
Cuff, J.A. and Barton, G.J. (2000) Application of multiple sequence alignment profiles to improve protein secondary structure prediction. Proteins, 40, 502–511[CrossRef][Web of Science][Medline].
Cuff, J.A., et al. (1998) JPred: a consensus secondary structure prediction server. Bioinformatics, 14, 892–893
Delsuc, F., et al. (2006) Tunicates and not cephalochordates are the closest living relatives of vertebrates. Nature, 439, 965–968[CrossRef][Medline].
Eddy, S.R. (1998) Profile hidden Markov models. Bioinformatics, 14, 755–763
Faisst, S. and Meyer, S. (1992) Compilation of vertebrate-encoded transcription factors. Nucleic Acids Res, . 20, 3–26
Friedman, J.R., et al. (1996) KAP-1, a novel corepressor for the highly conserved KRAB repression domain. Genes Dev, 10, 2067–2078
Goodstadt, L. and Ponting, C.P. (2001) CHROMA: consensus-based colouring of multiple alignments for publication. Bioinformatics, 17, 845–846
Hayashi, K., et al. (2005) A histone H3 methyltransferase controls epigenetic events required for meiotic prophase. Nature, 438, 374–378[CrossRef][Medline].
Huang, A., et al. (2005) Identification of a novel c-Myc protein interactor, JPO2, with transforming activity in medulloblastoma cells. Cancer Res, 65, 5607–5619
Huh, W.K., et al. (2003) Global analysis of protein localization in budding yeast. Nature, 425, 686–691[CrossRef][Medline].
Huntley, S., et al. (2006) A comprehensive catalog of human KRAB-associated zinc finger genes: Insights into the evolutionary history of a large family of transcriptional repressors. Genome Res, 16, 669–677
Kent, W.J. (2002) BLAT–the BLAST-like alignment tool. Genome Res, 12, 656–664
Lander, E.S., et al. (2001) Initial sequencing and analysis of the human genome. Nature, 409, 860–921[CrossRef][Medline].
Lim, F.L., et al. (1998) A KRAB-related domain and a novel transcription repression domain in proteins encoded by SSX genes that are disrupted in human sarcomas. Oncogene, 17, 2013–2018[CrossRef][Web of Science][Medline].
Looman, C., et al. (2002) KRAB zinc finger proteins: an analysis of the molecular mechanisms governing their increase in numbers and complexity during evolution. Mol. Biol. Evol, . 19, 2118–2130
Maertens, G.N., et al. (2006) Transcriptional co-activator p75 binds and tethers the Myc-interacting protein JPO2 to chromatin. J. Cell. Sci, . 119, 2563–2571
Marchler-Bauer, A. and Bryant, S.H. (2004) CD-Search: protein domain annotations on the fly. Nucleic Acids Res, . 32, W327–W331
Margolin, J.F., et al. (1994) Kruppel-associated boxes are potent transcriptional repression domains. Proc. Natl Acad. Sci. USA, 91, 4509–4513
Miller, J., et al. (1985) Repetitive zinc-binding domains in the protein transcription factor IIIA from Xenopus oocytes. EMBO J, . 4, 1609–1614[Web of Science][Medline].
Minsky, N. and Oren, M. (2004) The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression. Mol. Cell, 16, 631–639[CrossRef][Web of Science][Medline].
Pavletich, N.P. and Pabo, C.O. (1991) Zinc finger-DNA recognition: crystal structure of a Zif268-DNA complex at 2.1 A. Science, 252, 809–817
Pietrokovski, S. (1996) Searching databases of conserved sequence regions by aligning protein multiple-alignments. Nucleic Acids Res, . 24, 3836–3845
Ponting, C.P. and Russell, R.R. (2002) The natural history of protein domains. Annu. Rev. Biophys. Biomol. Struct, . 31, 45–71[CrossRef][Web of Science][Medline].
Ponting, C.P., et al. (1999) SMART: identification and annotation of domains from signalling and extracellular protein sequences. Nucleic Acids Res, . 27, 229–232
Rousseau-Merck, M.F., et al. (2002) The KOX zinc finger genes: genome wide mapping of 368 ZNF PAC clones with zinc finger gene clusters predominantly in 23 chromosomal loci are confirmed by human sequences annotated in EnsEMBL. Cytogenet. Genome Res, . 98, 147–153[CrossRef][Web of Science][Medline].
Sadreyev, R. and Grishin, N. (2003) COMPASS: a tool for comparison of multiple protein alignments with assessment of statistical significance. J. Mol. Biol, . 326, 317–336[CrossRef][Web of Science][Medline].
Schultz, D.C., et al. (2002) SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev, 16, 919–932
Schultz, J., et al. (2000) SMART: a web-based tool for the study of genetically mobile domains. Nucleic Acids Res, . 28, 231–234
Shannon, M., et al. (1998) Tandem zinc-finger gene families in mammals: insights and unanswered questions. DNA Seq, . 8, 303–315[Web of Science][Medline].
Sun, Z.W. and Allis, C.D. (2002) Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature, 418, 104–108[CrossRef][Medline].
Urrutia, R. (2003) KRAB-containing zinc-finger repressor proteins. Genome Biol, . 4, 231[CrossRef][Medline].
Waterston, R.H., et al. (2002) Initial sequencing and comparative analysis of the mouse genome. Nature, 420, 520–562[CrossRef][Medline].
Wootton, J.C. and Federhen, S. (1993) Statistics of local complexity in amino acid sequences and sequence databases. Comput. Chem, . 17, 149–163[CrossRef].
Wysocka, J., et al. (2005) WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell, 121, 859–872[CrossRef][Web of Science][Medline].
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Irie, A. Tsujimura, Y. Miyagawa, T. Ueda, Y. Matsuoka, Y. Matsui, A. Okuyama, Y. Nishimune, and H. Tanaka Single-Nucleotide Polymorphisms of the PRDM9 (MEISETZ) Gene in Patients With Nonobstructive Azoospermia J Androl, July 1, 2009; 30(4): 426 - 431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ding, P. Lorenz, M. Kreutzer, Y. Li, and H.-J. Thiesen SysZNF: the C2H2 zinc finger gene database Nucleic Acids Res., January 1, 2009; 37(suppl_1): D267 - D273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. R Copley The animal in the genome: comparative genomics and evolution Phil Trans R Soc B, April 27, 2008; 363(1496): 1453 - 1461. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-R. Chung, U. Lohr, and H. Jackle Lineage-specific expansion of the Zinc Finger Associated Domain ZAD Mol. Biol. Evol., September 1, 2007; 24(9): 1934 - 1943. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. I. Sadreyev, M. Tang, B.-H. Kim, and N. V. Grishin COMPASS server for remote homology inference Nucleic Acids Res., July 13, 2007; 35(suppl_2): W653 - W658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Goodstadt, A. Heger, C. Webber, and C. P. Ponting An analysis of the gene complement of a marsupial, Monodelphis domestica: Evolution of lineage-specific genes and giant chromosomes Genome Res., July 1, 2007; 17(7): 969 - 981. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||