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PubMed1983

Transcription of mouse mammary tumor virus: identification of a candidate mRNA for the long terminal repeat gene product.

We have examined an assortment of preneoplastic and neoplastic mouse mammary tissues for the presence of an mRNA which could encode the putative long terminal repeat gene product of mouse mammary tumor virus. We report here the detection of a novel mouse mammary tumor virus-specific, polyadenylic acid-containing transcript in certain preneoplastic and neoplastic mammary tissue of BALB/c mice. The molecule is 1.6 kilobases in length and contains sequences from the transcriptional leader and the U3 region of the proviral DNA. The upstream terminus of the 3' information lies 75 to 80 nucleotides from the beginning of the long terminal repeat open reading frame, in close proximity to a consensus splice acceptor in the DNA. The transcript was detected in hormonally or chemically induced neoplastic, preneoplastic, and lactating mammary tissue of BALB/c mice, but not in preneoplastic or tumor tissue induced by exogenous viruses in any strain of mice examined. This implies that the RNA we observed is transcribed from an endogenous provirus template.

Animals↗

PubMed2000

Expression of mitochondrial protein-coding genes in Tetrahymena pyriformis.

In the ciliate protozoon, Tetrahymena pyriformis, mitochondrial protein-coding genes are highly divergent in sequence, and in a number of cases they lack AUG initiation codons. We asked whether RNA editing might be acting to generate protein sequences that are more conventional than those inferred from the corresponding gene sequences, and/or to create standard AUG initiation codons where these are absent. However, comparison of genomic and cDNA sequences (the latter generated by reverse transcriptase sequencing of T. pyriformis mitochondrial mRNAs) yielded no evidence of mitochondrial RNA editing in this organism. To delineate the 5' ends of mitochondrial protein-coding transcripts, primer extension experiments were conducted. In all cases, 5' termini were found to map within a few nucleotides of potential initiation codons, indicating that T. pyriformis mitochondrial mRNAs have little or no 5' untranslated leader sequence. The pattern of strong primer extension stops suggested that both standard (AUG) and non-standard (AUU, AUA, GUG, UUG) initiation codons are utilized by the Tetrahymena mitochondrial translation system. We also investigated expression of the nad1 gene, which in both T. pyriformis and Paramecium aurelia is split into two portions that are encoded by and transcribed from different DNA strands. Northern hybridization analysis showed that the corresponding transcripts are not trans-spliced, implying that separate N-terminal and C-terminal portions of Nad1 are made in this system. Finally, in a search for primary transcripts, we isolated from a T. pyriformis mitochondrial fraction several small RNAs that were reproducibly labeled by incubation in the presence of [alpha-(32)P]GTP and guanylyltransferase. Partial sequence information revealed that none of these cappable RNAs is encoded in the T. pyriformis mitochondrial genome.

5' Untranslated Regions↗

PubMed1989

Characterization of the spliced leader genes and transcripts in Trypanosoma cruzi.

Trypanosome mRNA is processed to maturity in a novel trans-splicing reaction during which a 35-nucleotide (nt) spliced leader (SL) is joined to the 5' ends of most structural gene transcripts. We have examined this process in Trypanosoma cruzi, the causative agent of Chagas' disease in Central and South America. In this communication, we characterize the genes encoding the SL (SL gene) in five different strains of T. cruzi by hybridization analysis and show that the genome of each of these strains contains numerous tandemly repeated copies of the SL gene. We demonstrate that the SL genes show remarkable intrastrain homogeneity, but significant interstrain heterogeneity. We have cloned and sequenced one of the SL repeats from T. cruzi strain CL and used synthetic oligodeoxyribonucleotides designed to hybridize to SL gene transcripts in Northern analyses of T. cruzi RNA to identify an approx. 110-nt putative SL primary transcript (SL-RNA). The 5' end of the SL-RNA was mapped to the first nt of the SL by primer extension analyses. The sequence of the 110-nt SL-RNA was used to generate a predicted secondary structure, and this structure compared favorably to the predicted secondary structures of SL transcripts of other trypanosomatids.

Animals↗

PubMed1997

Mitofilin is a transmembrane protein of the inner mitochondrial membrane expressed as two isoforms.

Mitofilin, also known as heart muscle protein, is a recently identified mitochondrial protein. We have isolated two human cDNAs that encode different isoforms of mitofilin. Using reverse PCR, we provide evidence that both isoforms are derived by alternative splicing and encode two proteins of 88 and 90 kDa that are detected in immunoblot analyses with mitofilin-specific antibodies. Immunofluorescence microscopy, fractionating of human osteosarcoma cells, and protease protection experiments with isolated mitochondria and mitoplasts indicate that mitofilin is an integral membrane protein of the inner mitochondrial membrane. 35S-labeled mitofilin is transported into isolated yeast mitochondria in a reaction that depends on the membrane potential across the inner mitochondrial membrane (delta psi). During mitochondrial in vitro import, mitofilin is proteolytically processed to the mature protein that is also detected in cellular fractions, indicating that the amino-terminal leader sequence is removed. Sequence analysis and our results suggest that mitofilin is anchored in the inner mitochondrial membrane with an amino-terminal transmembrane domain, while the majority of the protein is extruding into the intermembrane space.

Amino Acid Sequence↗

PubMed1984

Avian sarcoma virus gag and env gene structural protein precursors contain a common amino-terminal sequence.

The initiation site for translation of the avian sarcoma virus glycoprotein precursor, Pr63env, has been determined by analyzing the amino-terminal peptides of Pr63env and the polyprotein precursor Pr76gag encoded by the viral gag gene. The acceptor splice junction used to form the env gene mRNA has also been identified. Hybrid-selected virus-specific mRNAs were translated in vitro in the presence of either L-[35S]methionine to label at every methionine residue or L-[35S]methionine-tRNAMeti to label specifically at the amino-terminal methionine residues. Tryptic peptide maps of Pr63env labeled at every methionine residue contain all of the peptides, plus one additional peptide, present in the map of Pr57env, a nonglycosylated env-encoded polypeptide of molecular weight 57,000 immunoprecipitated from tunicamycin-treated cells. Specific amino-terminal labeling of the in vitro-synthesized polypeptides showed that the peptide missing from Pr57env corresponds to the amino-terminal tryptic peptide of Pr63env, which is removed in vivo as part of the amino-terminal signal peptide. Comparison of the amino-terminal tryptic peptides of Pr63env and Pr76gag showed that they are identical. In contrast, the chymotryptic amino-terminal peptides of Pr76gag and Pr63env are not identical. The location of the acceptor-splice junction in the env mRNA of the Prague A strain of avian sarcoma virus was determined by mung bean nuclease mapping to be at nucleotide 5,078. Fusion of the gag and env gene sequences during splicing results in use of the same AUG codon to initiate synthesis of Pr76gag and Pr63env. This sequence is contained within the 397-nucleotide 5' terminal leader that is spliced to the body of the env mRNA. The possible significance of these results for the regulation of avian sarcoma virus synthesis and translation is discussed.

Amino Acid Sequence↗

PubMed1998

Processing of vertebrate box C/D small nucleolar RNAs in plant cells.

The recent isolation of a number of plant box C/D small nucleolar (sno)RNAs demonstrates the conservation in plants of sequence and structural elements of processed box C/D snoRNAs. Boxes C and D, and terminal inverted repeats are known to be essential for accumulation and processing in vertebrates and yeast. Processing of vertebrate box C/D snoRNAs was examined by expression of various mouse hsc70 intron 5-U14 constructs in tobacco protoplasts. Full-length U14 and internally deleted U14 accumulated in the plant cells. Human U3 and U8 fragments, consistent with processing to internal box C/C' sequences, also accumulated in the plant cells. The similarity of processing behaviour of the vertebrate box C/D constructs in tobacco protoplasts and Xenopus oocytes suggests the mechanism of processing, involving recognition and association of proteins, is conserved in plants.

Animals↗

PubMed1980

An unusual translocation of immunoglobulin gene segments in variants of the mouse myeloma MPC11.

Immunoglobulin light chain genes of the mouse are composed in germ-line DNA of four separate segments, the leader, V (variable), J (joining) and C (constant) segments. In immunocompetent cells a V and J gene segment are joined by a site-specific recombination event. In variants of the mouse myeloma MPC11 a so-called kappa (k) light chain fragment is expressed which consists of the MOPC321 leader peptide, joined to the kappa constant region peptide. Using the Southern blotting technique we found that the gene coding for the light chain fragment has apkparently been generated by an aberrant translocation of a V gene segment identical or very similar to the MOPC321 V gene segment into the large intervening sequence between the J and the C gene segments. The resulting deletion of the splice signals of the J segments could be the reason for the observed splicing between leader and C region sequences, a phenomenon which may be of general interest for the understanding of the splicing mechanism.

Animals↗

PubMed1987

Overproduction of polyomavirus middle T antigen in mammalian cells through the use of an adenovirus vector.

To overproduce biologically active polyomavirus middle T antigen, we used an adenovirus vector and human 293 cells as hosts. Two helper-independent recombinant adenoviruses were isolated that contain a hybrid transcription unit, in differing orientations, at a site in the adenovirus genome from which the E1a and most of the E1b transcription units have been deleted. The hybrid transcription unit consists of the adenovirus type 2 major late promoter and tripartite leader and a cDNA segment capable of encoding polyomavirus middle T antigen and accompanying 3' RNA-processing signals. Both recombinant viruses were stable and replicated to high titers in human 293 cells. The polyomavirus sequences were expressed, predominantly at late times after infection of 293 cells, to yield mRNAs that encoded middle T antigen. One of the recombinant viruses also expressed a middle T antigen-related protein in 293 cells. The latter was translated from one of several novel mRNA species that resulted from aberrant splicing and incomplete RNA processing of precursor RNA transcripts. Comparison of the amount of middle T antigen produced in 3T6 cells infected with polyomavirus with that in 293 cells infected with either of the recombinant adenoviruses, under optimal conditions for each system, revealed at least a 10-fold greater yield of the protein on a per-cell basis in the latter system than in the former. The recombinant-virus-encoded middle T antigen was biologically active, as evidenced by its ability to associate with and serve as a substrate for human pp60c-src. The functionality of the middle T antigen was further confirmed by demonstrating that both recombinant viruses efficiently transformed Rat-1 cells. These recombinant viruses will be useful to overproduce middle T antigen and to introduce the polyomavirus oncogene into a wide variety of mammalian cells.

Adenoviruses, Human↗

PubMed1982

Detailed structural analysis of two spliced HSV-1 immediate-early mRNAs.

The structures of two HSV-1 immediate-early mRNAs have been determined by nuclease-digestion procedures using 5' and 3' end-labelled DNA probes. These mRNAs, which map across the junctions between the short unique (US) and short repeat (IRS and TRS) genome regions, have common 5' portions located in IRS and TRS. The 3' portions, which extend into opposite ends of US, and unique. The DNA sequence encoding the common 5' portions largely comprises a 247 base pair (bp) leader region and a single intron of variable size. The variation in intron length is due to different copy numbers of a 22 bp tandem reiteration. A small proportion of the mRNA population is unspliced, but otherwise is identical to the more abundant spliced species.

Animals↗

PubMed2001

Influence of the small leader exons 2 and 3 on human immunodeficiency virus type 1 gene expression.

The human immunodeficiency virus type 1 (HIV-1) uses an elaborate alternative splicing pattern for the generation of both the 1.8-kb as well as the 4-kb classes of mRNA. An additional diversity of transcripts in both classes is created by the optional inclusion of the small exons 2 and 3 in the leader sequence. To analyze a possible influence of these leader exons on HIV-1 gene expression, several series of expression vectors with different leaders were constructed, expressing either Rev and Env or a heterologous coding sequence, i.e., the chloramphenicol acetyl transferase (CAT) ORF. Transfection experiments of HeLa-T4(+) cells revealed for all series of constructs that mRNA as well as protein expression was stimulated by the presence of exon 2 and reduced by exon 3. The function of the leader exons 2 and 3 is neither dependent on the regulatory proteins Tat or Rev nor on viral coding sequences. Neither transcription rates nor stability of polyadenylated RNAs were found to be responsible for the different levels of steady-state mRNA. When either exon 2 or 3 was inserted into a heterologous intron, processing of the primary transcripts generated identical mRNA species while maintaining the differences in exon 2/3-dependent mRNA steady-state levels. These results may be explained by exon-specific nuclear RNA degradation rates, as also indicated by results from an in vitro degradation assay using a HeLa nuclear extract.

Alternative Splicing↗

PubMed1995

Structure and expression of Euglena gracilis nuclear rbcS genes encoding the small subunits of the ribulose 1,5-bisphosphate carboxylase/oxygenase: a novel splicing process for unusual intervening sequences?

In the protist Euglena gracilis, the small subunit of the chloroplast enzyme ribulose 1,5-bisphosphate carboxylase/oxygenase is encoded by nuclear rbcS genes and synthesized as a polyprotein precursor containing eight mature small subunit molecules. This large precursor is encoded by at least eight different nuclear genes as ascertained by transcript analysis. The structure of three rbcS genes was established and the coding sequences were found to be interrupted by many intervening sequences (IVS). Apart from the first 5' intron involved in trans-splicing, none of these IVSs obeys the GT-AG rule characteristic of introns in higher eukaryote genes. Surprisingly, these IVSs are located at identical positions within the three genes studied. Moreover, extensive sequence homologies were found between IVSs located in the same gene as well as in different genes. The sequences of these homologous IVSs differ only by inserted and/or deleted sequences. The striking conservation of the 5' and 3' regions of these IVSs is correlated to their potential secondary structures. These structures, which bring the IVS extremities together with the exon boundaries, could be involved in a novel splicing process. The second 5' IVS is shown to be excised before the addition of the spliced leader sequence to the pre-mRNA. Similarly, two 3' IVSs are excised before the polyadenylation step. These results suggest that IVS splicing is faster than eukaryotic genomic cis-splicing and involves components other than those of the classical spliceosomes.

Amino Acid Sequence↗

PubMed2004

Internal ribosome entry site structural motifs conserved among mammalian fibroblast growth factor 1 alternatively spliced mRNAs.

Fibroblast growth factor 1 (FGF-1) is a powerful angiogenic factor whose gene structure contains four promoters, giving rise to a process of alternative splicing resulting in four mRNAs with alternative 5' untranslated regions (5' UTRs). Here we have identified, by using double luciferase bicistronic vectors, the presence of internal ribosome entry sites (IRESs) in the human FGF-1 5' UTRs, particularly in leaders A and C, with distinct activities in mammalian cells. DNA electrotransfer in mouse muscle revealed that the IRES present in the FGF-1 leader A has a high activity in vivo. We have developed a new regulatable TET OFF bicistronic system, which allowed us to rule out the possibility of any cryptic promoter in the FGF-1 leaders. FGF-1 IRESs A and C, which were mapped in fragments of 118 and 103 nucleotides, respectively, are flexible in regard to the position of the initiation codon, making them interesting from a biotechnological point of view. Furthermore, we show that FGF-1 IRESs A of murine and human origins show similar IRES activity profiles. Enzymatic and chemical probing of the FGF-1 IRES A RNA revealed a structural domain conserved among mammals at both the nucleotide sequence and RNA structure levels. The functional role of this structural motif has been demonstrated by point mutagenesis, including compensatory mutations. These data favor an important role of IRESs in the control of FGF-1 expression and provide a new IRES structural motif that could help IRES prediction in 5' UTR databases.

5' Untranslated Regions↗

PubMed1995

Dimerization of HIV-1Lai RNA at low ionic strength. An autocomplementary sequence in the 5' leader region is evidenced by an antisense oligonucleotide.

Genomic human immunodeficiency virus type 1 (HIV-1) RNA consists of two identical RNA molecules joined noncovalently near their 5' ends in a region called the dimer linkage structure (DLS). Previous work has shown that the putative DLS is localized in a 113-nucleotide domain encompassing the 5' end of the gag gene. This region contains conserved purine tracks that are thought to mediate dimerization through purine quartets. However, recently, an HIV-1Mal RNA dimerization model was proposed as the HIV-1Mal RNA dimerization initiation site, involving another region upstream from the splice donor site and possibly confined within a stem-loop. In the present study, we have investigated the dimerization of HIV-1Lai RNA, using in vitro dimerization assays under conditions of low ionic strength, predictive RNA secondary structures determined by computer folding, and antisense DNA oligonucleotides in order to discriminate between these two models. Our results suggest that purine quartets are not involved in the dimer structure of HIV-1Lai RNA and have led to the identification of a region upstream from the splice donor site. This region, comprising an autocomplementary sequence in a possible stem-loop structure, is responsible for the formation of dimeric HIV-1Lai RNA.

Base Sequence↗

PubMed2006

The strength of the HIV-1 3' splice sites affects Rev function.

BACKGROUND: The HIV-1 Rev protein is a key component in the early to late switch in HIV-1 splicing from early intronless (e.g. tat, rev) to late intron-containing Rev-dependent (e.g. gag, vif, env) transcripts. Previous results suggested that cis-acting sequences and inefficient 5' and 3' splice sites are a prerequisite for Rev function. However, we and other groups have shown that two of the HIV-1 5' splice sites, D1 and D4, are efficiently used in vitro and in vivo. Here, we focus on the efficiency of the HIV-1 3' splice sites taking into consideration to what extent their intrinsic efficiencies are modulated by their downstream cis-acting exonic sequences. Furthermore, we delineate their role in RNA stabilization and Rev function. RESULTS: In the presence of an efficient upstream 5' splice site the integrity of the 3' splice site is not essential for Rev function whereas an efficient 3' splice site impairs Rev function. The detrimental effect of a strong 3' splice site on the amount of Rev-dependent intron-containing HIV-1 glycoprotein coding (env) mRNA is not compensatable by weakening the strength of the upstream 5' splice site. Swapping the HIV-1 3' splice sites in an RRE-containing minigene, we found a 3' splice site usage which was variably dependent on the presence of the usual downstream exonic sequence. The most evident activation of 3' splice site usage by its usual downstream exonic sequence was observed for 3' splice site A1 which was turned from an intrinsic very weak 3' splice site into the most active 3' splice site, even abolishing Rev activity. Performing pull-down experiments with nuclear extracts of HeLa cells we identified a novel ASF/SF2-dependent exonic splicing enhancer (ESE) within HIV-1 exon 2 consisting of a heptameric sequence motif occurring twice (M1 and M2) within this short non-coding leader exon. Single point mutation of M1 within an infectious molecular clone is detrimental for HIV-1 exon 2 recognition without affecting Rev-dependent vif expression. CONCLUSION: Under the conditions of our assay, the rate limiting step of retroviral splicing, competing with Rev function, seems to be exclusively determined by the functional strength of the 3' splice site. The bipartite ASF/SF2-dependent ESE within HIV-1 exon 2 supports cross-talk between splice site pairs across exon 2 (exon definition) which is incompatible with processing of the intron-containing vif mRNA. We propose that Rev mediates a switch from exon to intron definition necessary for the expression of all intron-containing mRNAs.

3' Untranslated Regions↗

PubMed1992

Diversity of novel recombining elements suggests developmentally programmed expression of the T cell receptor alpha/delta locus.

During fetal ontogeny, the first wave of gamma delta T lymphocytes appears in the thymus at day 14 of gestation assembling predominantly T cell receptors (TcR) with V gamma 3 and V delta 1. To identify V delta gene segments that are transcribed at day 16, subsequent to the first wave of V delta 1 expression, delta chain cDNA was amplified by the anchored polymerase chain reaction with single-sided specificity for C delta. Unexpectedly, most of the cDNA clones do not contain V gene segments. In some cDNA clones an alternative splice from the leader exon to the C delta exon has deleted the whole variable region exon. In other cDNA clones, multiple non-V-like elements are juxtaposed to the D delta 2 and J delta 1 gene segments. A large number of these diverse elements appear to be rearranged in fetal thymocytes, bringing V alpha gene segments located upstream of the recombining element into proximity to the J alpha locus. It is proposed that these rearrangements make irreversible the commitment to the TcR alpha beta lineage and determine a programmed read out of different clusters of V alpha gene segments.

Animals↗

PubMed1998

Functional comparison of the yeast scERV1 and scERV2 genes.

The yeast scERV1 gene is the first representative of a new emerging gene family. Its gene product is essential for the yeast cell and is involved in the biogenesis of mitochondria and the regulation of the cell cycle. Recently the general importance of the gene for the eukaryotic cell was shown by the identification of a structural and functional human homologue. The homologous mammalian ALR (augmenter of liver regeneration) genes from man, mouse and rat are important for different developmental stages of the organism as for example in spermatogenesis and the regeneration of damaged liver organs. Latest research identified an intron with an unusual 3' branch site in the 5' region of the yeast scERV1 gene. Analysis of the now available complete genome sequence from Saccharomyces cerevisiae identified a second yeast gene with homologies to scERV1 on chromosome 16. The corresponding gene product has a length of 196 amino acids similar to the 189 residues of the scERV1 protein and exhibits 30% identical amino acid residues in the highly conserved carboxy-terminal part of the polypeptides. Because of the structural similarities the new gene will be termed scERV2 from now on. For the scERV1 gene product it has just been shown that it is associated with yeast mitochondria. Analysis of the amino-terminal part of the putative scERV2 protein also identifies a typical leader sequence for import into mitochondria. The comparison of cDNA and genomic DNA from the scERV2 gene shows that no intron is present in this gene. To investigate the functional relation between the two yeast genes disruption experiments and complementation studies of mutants from scERV1 were performed. In addition the expression of messenger RNA under 15 different growth conditions was investigated by detailed Northern hybridization studies. Both genes show a complex and distinct expression pattern for their transcripts and are highly regulated under different physiological conditions. Moreover correct and efficient splicing of the transcript from the scERV1 gene was found to vary with the physiological state of the yeast cell, as further verified by reverse transcription-polymerase chain reaction analysis of transcripts from galactose-grown yeast cells.

Blotting, Northern↗

PubMed1990

Intervening sequences increase efficiency of RNA 3' processing and accumulation of cytoplasmic RNA.

Two expression vectors were constructed that differ only in the presence (+) or absence (-) of an intervening sequence (IVS) in their 5'-untranslated leaders. Transient transfection into four mammalian cell lines resulted in higher levels of the indicator protein (CAT) from the IVS(+) vector (6 to 50-fold). Cytoplasmic RNA concentrations in 293s and HeLa cell lines corresponded directly to resultant protein levels; measurements in 293s cells of transcription initiation and elongation, steady-state total nuclear RNA, and cytoplasmic RNA stability, were equivalent for the two vectors. Surprisingly, the amount of poly(A)+ nuclear RNA was greater from the IVS(+) vector. Since this difference matches the ratio seen with polyadenylated cytoplasmic RNA, our results imply that splicing is coupled to a polyadenylation/transport pathway.

Animals↗

PubMed1995

Rat growth hormone receptor/growth hormone-binding protein mRNAs with divergent 5'-untranslated regions are expressed in a tissue-specific manner.

In the rat, the growth hormone receptor (GH-R) gene generates two transcripts, one encoding the transmembrane GH-R, and a shorter one encoding the GH-binding protein (GH-BP). These transcripts exhibit a high degree of heterogeneity in their 5'-untranslated regions (5'-UTRs). Some of the exons encoding these 5'-UTR variants may be flanked by distinct promoter regions whose activity would result in the tissue-specific expression of the GH-R gene. To assess this possibility, we used single-sided polymerase chain reaction (PCR) amplification to characterize 5'-UTR variants in rat GH-R cDNAs, and by using 5'-UTR-specific probes, we determined their pattern of expression in several tissues. Besides two previously described variants (V1 and V2), three new 5'-UTR variants were identified, extending 56 nucleotides (V3), 135 nucleotides (V4), and 209 nucleotides (V5) upstream of the ATG translation initiation codon. The expression of GH-R and GH-BP transcripts was clearly tissue specific. In the liver, GH-BP mRNA was the predominant transcript, whereas in other tissues, there was equivalent expression of both transcripts or predominant expression of GH-R mRNA. With respect to the tissue distribution of the 5'-UTR variants in particular, variants V1 and V5 exhibited a pattern of expression closely resembling that seen with an exon 2 probe, with the overall expression of variant V1 being much higher than that of variant V5. The V2 species was exclusively expressed in liver. Variant V3 was expressed at low levels in liver, muscle, heart, and kidney; in muscle and heart, it was preferentially associated with GH-BP transcripts. Variant V4, although present in liver, was more abundant in extrahepatic tissues and predominantly found in GH-R mRNA transcripts. Southern blot analyses were consistent with exon 2 and the exons encoding the V1 and V2 sequences being in proximity, with the other 5'-UTR sequences being encoded by exons located further upstream of exon 2. These findings support the concept that different 5'-UTR variants are the result of the different promoters acting in a tissue-specific manner. The association of specific 5'-UTR variants with either GH-R or GH-BP transcripts raises the possibility that the alternative splicing process that generates GH-BP mRNA in the rat might be controlled by the 5'-flanking region regulating the expression of specific leader exons.

Animals↗