Complete sequencing of the
            <i>Fugu</i>
            WAGR region from WT1 to PAX6: Dramatic compaction and conservation of synteny with human chromosome 11p13

Miles, Colin M.; Elgar, Greg; Coles, Edward G.; Kleinjan, Dirk-Jan; Heyningen, Veronica van; Hastie, Nicholas D.

doi:10.1073/pnas.95.22.13068

Cited by 110 publications

(86 citation statements)

References 32 publications

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“…Further studies will be required to con®rm these preliminary results, but this is consistent with several reports of conserved non-coding sequences, between Fugu and human genes, located in promoters, 3' UTR and even introns How et al, 1996;Kimura et al, 1997;Rowitch et al, 1998;Miles et al, 1998;Gellner and Brenner 1999). Some of them have been shown to have functional signi®cance in vivo Kimura et al, 1997;Rowitch et al, 1998).…”

supporting

confidence: 70%

Comparative analysis of the ETV6 gene in vertebrate genomes from pufferfish to human

Montpetit

Sinnett

2001

Oncogene

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The ETV6 gene encodes an Ets-like transcription factor that is frequently rearranged in leukemias. While some of the functions of ETV6 have been uncovered recently, little is known about the key structural elements involved. Comparative genome analysis may provide novel insights into gene evolution and functions. In this study, we cloned and sequenced the homologue of ETV6 from the compact genome of the pu er®sh Fugu rubripes (fETV6). The genomic structure of the fETV6 gene was investigated by sequence analysis of a contig of genomic clones. The fETV6 gene, composed of eight exons, spans about 15 kb and is 16 times smaller than its human counterpart mainly because of the reduced intron size. Three of the seven introns of fETV are unusually large (more than 2 kb), including the 8.2 kb intron 2. The gene codes for a protein of 465 amino acids that is highly related to its human homologue, exhibiting an overall identity of 58% (72% similarity). To investigate the functional and evolutionary aspects of ETV6, we undertook a comparative analysis of this gene from various vertebrates (human, mouse, chicken, zebra®sh and Fugu). As expected, the PNT and ETS domains were highly conserved, with on average 81 and 95% peptide sequence identity, respectively. In addition, we found several new highly conserved regions within the central section of the protein that are likely to represent further functional or structural domains, which may be associated with the transcription repression capacity of this protein. We also found conserved putative regulatory elements in the promoter as well as in the large intron 2 of fETV6. The information derived from this comparative analysis will serve as the basis for more precise functional studies of ETV6 gene regulation and function. Oncogene (2001) 20, 3437 ± 3442.

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supporting

confidence: 70%

Comparative analysis of the ETV6 gene in vertebrate genomes from pufferfish to human

Montpetit

Sinnett

2001

Oncogene

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“…No clear domain structure could be identified on the basis of these homologies. Interestingly, however, the putative human and mouse Elp4 proteins are encoded by the human and mouse PAXNEB gene, respectively, which is localized on human chromosome 11p13 (mouse chromosome 2), a region implicated with human disease (20). PAXNEB is expressed in a variety of human tissues as determined by Northern blot analysis (Fig.…”

Section: Identification Of Elp4 Homologues In Higher Eukaryotes-mentioning

confidence: 99%

RNA Polymerase II Elongator Holoenzyme Is Composed of Two Discrete Subcomplexes

Winkler¹,

Petrakis²,

Ethelberg³

et al. 2001

Journal of Biological Chemistry

159

193

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Elongator is a histone acetyltransferase complex that associates with the elongating form of RNA polymerase II. We purified Elongator to virtual homogeneity via a rapid three-step procedure based largely on affinity chromatography. The purified factor, holo-Elongator, is a labile six-subunit factor composed of two discrete subcomplexes: one comprised of the previously identified Elp1, Elp2, and Elp3 proteins and another comprised of three novel polypeptides, termed Elp4, Elp5, and Elp6. Disruption of the yeast genes encoding the new Elongator proteins confers phenotypes indistinguishable from those previously described for the other elp mutants, and concomitant disruption of genes encoding proteins in either subcomplex does not confer new phenotypes. Taken together, our results indicate that holo-Elongator is a functional entity in vitro as well as in vivo. Metazoan homologues of Elp1 and Elp3 have previously been reported. We cloned the human homologue of yeast ELP4 and show that this gene is ubiquitously expressed in human tissues.The form of RNA polymerase II (RNAPII) 1 responsible for transcript elongation is fundamentally different from the form that enters a promoter to form a preinitiation complex (1, 2). During initiation, RNAPII is hypo-phosphorylated and associated with the functionally conserved Mediator complex, a multisubunit factor required for regulation of transcription (3, 4). The association of RNAPII with Mediator and the general transcription factors is severed during promoter clearance, triggered by TFIIH-mediated hyperphosphorylation of the carboxyl-terminal repeat domain (CTD) of the largest RNAPII subunit (5-7). During elongation, hyperphosphorylated yeast RNAPII is associated with the Elongator complex. Elongator binds directly to RNAPII, at least partly via the CTD, and the interaction is stabilized by CTD hyperphosphorylation (8).

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“…The e5a-containing isoform, PAX6(5a), is specific to and conserved in vertebrates (9). Pax6 is expressed in the developing eye, nose, pancreas, and central nervous system (7,(10)(11)(12)(13).…”

mentioning

confidence: 99%

Iris hypoplasia in mice that lack the alternatively spliced Pax6(5a) isoform

Singh

Shukla

Arango

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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PAX6 is an evolutionarily conserved transcription factor that plays a critical role in vertebrate and invertebrate eye formation. Heterozygous null mutations in the PAX6 gene result in aniridia in humans and a distinct small eye syndrome in rodents. Vertebrates primarily express two alternatively spliced isoforms of Pax6 that differ by the presence or absence of exon 5a (e5A) that encodes an additional 14 aa residues within the paired domain. The e5a-containing isoform, PAX6(5a), is specific to and conserved in vertebrates. To determine the role of PAX6(5a), we have generated mice that lack e5a of the Pax6 gene. Unlike Pax6 null mice that exhibit anopthalmia with central nervous system defects and lethality, 5a isoform-null mice have iris hypoplasia and defects in the cornea, lens, and retina. Although invertebrates have structures that respond to light intensity and act to restrict light exposure of the eyes, a significant and distinct feature of the vertebrate eye is its ability to regulate the amount of incoming light through contractile pupils. This feature of the eye not only allows vertebrates to see in various light conditions but also enhances image resolution. The requirement of the 5a isoform in iris formation suggests that the evolution of this isoform contributed to advanced features of the vertebrate eye. P AX6 is an essential and evolutionarily conserved transcription factor for eye formation (1-3). Heterozygous null mutations in the PAX6 gene result in distinct phenotypes in humans (aniridia) and rodents (small eye) (4, 5). Aniridia is a severe panocular disease that is characterized by lack of proper iris development, associated with cataracts, optic nerve hypoplasia, and glaucoma. Small eye syndrome is distinguished from aniridia by reduced eye size, cataracts, and poor lens development. Homozygous mutations in the PAX6 gene result in severe brain abnormalities, microencephaly, early postnatal death, and the absence of the eyes and nose in both humans (4) and rodents (5, 6).The Pax6 locus encodes two products caused by alternative splicing of exon 5a (e5a) that adds an additional 14 aa residues within the paired domain (7,8). The e5a-containing isoform, PAX6(5a), is specific to and conserved in vertebrates (9). Pax6 is expressed in the developing eye, nose, pancreas, and central nervous system (7, 10-13). PAX6 is a protein of 422 aa residues, and PAX6(5a) is 14 aa longer and exhibits unique DNA-binding properties (14). Structural analysis of PAX6 identified two DNA-binding domains (a paired domain at the amino terminus and a paired-like homeodomain located centrally), a glycine-rich region that links the two DNA-binding domains, and a transactivation domain at the carboxyl terminus. The paired domain of PAX6 is a bipartite DNA-binding motif and is believed to have two independent amino-terminal and carboxyl-terminal subdomains (15, 16). The paired domain can bind DNA alone or cooperatively by interacting with other DNA-binding domains, such as the homeodomain (17). Unlike other paired domains th...

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Complete sequencing of the Fugu WAGR region from WT1 to PAX6: Dramatic compaction and conservation of synteny with human chromosome 11p13

Cited by 110 publications

References 32 publications

Comparative analysis of the ETV6 gene in vertebrate genomes from pufferfish to human

Comparative analysis of the ETV6 gene in vertebrate genomes from pufferfish to human

RNA Polymerase II Elongator Holoenzyme Is Composed of Two Discrete Subcomplexes

Iris hypoplasia in mice that lack the alternatively spliced Pax6(5a) isoform

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