The Cathepsin L First Intron Stimulates Gene Expression in Rat Sertoli Cells1

Charron, Martin; Chern, Jing Yi; Wright, William W.

doi:10.1095/biolreprod.106.057851

Cited by 21 publications

(19 citation statements)

References 62 publications

(89 reference statements)

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“…In addition, repeats in first introns were associated with greater expression divergence than repeats in other introns. This observation is consistent with previous work showing that most intronic regulatory regions occur in the first intron (Rohrer and Conley 1998), that the first intron has the highest divergence between human and chimpanzees (Gazave et al 2007), and that the first intron influences gene expression more than other introns (Jonsson et al 1992;Charron et al 2007).…”

Section: Discussionsupporting

confidence: 93%

Tandem repeat variation in human and great ape populations and its impact on gene expression divergence

et al. 2015

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Tandem repeats (TRs) are stretches of DNA that are highly variable in length and mutate rapidly. They are thus an important source of genetic variation. This variation is highly informative for population and conservation genetics. It has also been associated with several pathological conditions and with gene expression regulation. However, genome-wide surveys of TR variation in humans and closely related species have been scarce due to technical difficulties derived from short-read technology. Here we explored the genome-wide diversity of TRs in a panel of 83 human and nonhuman great ape genomes, in a total of six different species, and studied their impact on gene expression evolution. We found that population diversity patterns can be efficiently captured with short TRs (repeat unit length, 1–5 bp). We examined the potential evolutionary role of TRs in gene expression differences between humans and primates by using 30,275 larger TRs (repeat unit length, 2–50 bp). Genes that contained TRs in the promoters, in their 3′ untranslated region, in introns, and in exons had higher expression divergence than genes without repeats in the regions. Polymorphic small repeats (1–5 bp) had also higher expression divergence compared with genes with fixed or no TRs in the gene promoters. Our findings highlight the potential contribution of TRs to human evolution through gene regulation.

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Section: Discussionsupporting

confidence: 93%

Tandem repeat variation in human and great ape populations and its impact on gene expression divergence

et al. 2015

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“…The inclusion of just one intron near the 5′ end of the gene increases transcription of the gene many folds. A number of mammalian genes, including β-globin, growth hormone, thymidylate synthase, purine nucleoside phosphorylase, cathepsin L, and HIV-1 require introns for their normal expression (7)(8)(9)(10)(11)(12)(13)(14). A similar intron-dependent stimulation of transcription has been observed in a variety of genes in plants (6, 15).…”

mentioning

confidence: 78%

“…In contrast, splicing-dependent regulation of transcription requires a functional, splicing-competent intron within the body of the gene. Such introns cannot affect transcription if their splicing is compromised by a mutation in the conserved sequences at the 5′ splice site, 3′ splice site, branchpoint or if they are inserted in an antisense orientation (8,17). This direct effect of introns on transcription of genes is often referred to as "intron-mediated enhancement" (IME) and will be the focus of this investigation (6).…”

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confidence: 99%

Role for gene looping in intron-mediated enhancement of transcription

Moabbi

Agarwal

Kaderi

et al. 2012

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

103

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Intron-containing genes are often transcribed more efficiently than nonintronic genes. The effect of introns on transcription of genes is an evolutionarily conserved feature, being exhibited by such diverse organisms as yeast, plants, flies, and mammals. The mechanism of intron-mediated transcriptional activation, however, is not entirely clear. To address this issue, we inserted an intron in INO1, which is a nonintronic gene, and deleted the intron from ASC1, which contains a natural intron. We then compared transcription of INO1 and ASC1 genes in the presence and absence of an intron. Transcription of both genes was significantly stimulated by the intron. The introns have a direct role in enhancing transcription of INO1 and ASC1 because there was a marked increase in nascent transcripts from these genes in the presence of an intron. Intron-mediated enhancement of transcription required a splicing competent intron. Interestingly, both INO1 and ASC1 were in a looped configuration when their genes contained an intron. Intron-dependent gene looping involved a physical interaction of the promoter and the terminator regions. In addition, the promoter region interacted with the 5′ splice site and the terminator with the 3′ splice site. Intron-mediated enhancement of transcription was completely abolished in the looping defective sua7-1 strain. No effect on splicing, however, was observed in sua7-1 strain. On the basis of these results, we propose a role for gene looping in intron-mediated transcriptional activation of genes in yeast.chromosome conformation capture | RNA polymerase II T he protein encoding genes in eukaryotes differ from their prokaryotic counterparts in having noncoding intervening regions called introns, which are removed by splicing to generate mature mRNA. Since their discovery in 1977, there has been considerable debate regarding the functional role of introns in eukaryotes (1). It is widely believed that introns increase proteomic complexity by facilitating expression of multiple proteins from a single gene by alternative splicing (2). In budding yeast, where more than 95% of genes are without introns and there are very few instances of alternative splicing, introns do not contribute significantly to the proteomic diversity (3). The presence of introns in all eukaryotes, despite the high cost of maintaining them and the existence of the elaborate splicing machinery needed to remove them, suggest that introns are playing a more fundamental and evolutionarily conserved role in eukaryotic cells.One role of introns that has been remarkably conserved among diverse organisms, and which confers an additional advantage to eukaryotic genes, is their effect on efficiency of gene expression (4-6). Introns significantly enhance the transcriptional output of genes that harbor them. The expression level of intronless transgenes in mammalian cells is often 10-100 times lower than their intron-containing counterparts (5). The inclusion of just one intron near the 5′ end of the gene increases transcription of th...

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“…However, introns are also required for optimal gene expression in many systems, including yeast, plants, insects, mammalian tissue culture cells, and transgenic mice. 13,[15][16][17][18][19][20][21][22][23][24][25][26][27][28] In some cases, intron-dependent gene expression is mediated by transcriptional control elements. For example, previous studies in transgenic mice have implicated a role for intronic enhancers in mediating the expression of vascular endothelial growth factor receptor 2, Tie2, GATA2, and endoglin.…”

Section: Discussionmentioning

confidence: 99%

“…13,14,26 Also, the requirement for intronic splicing depends on the identity of the promoter. 24,50 For example, introns were shown to be important for expression from immunoglobulin or b-globin promoters, but not from a heat shock promoter. 50 Consistent with these data, we demonstrated that the first intron of vWF was unable to augment expression of the Tie2-luciferase construct in transient transfections.…”

Section: Discussionmentioning

confidence: 99%

Role of RNA splicing in mediating lineage-specific expression of the von Willebrand factor gene in the endothelium

Yuan

Janes

Beeler

et al. 2013

Blood

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Key Points• RNA splicing of the first intron of the von Willebrand factor gene is essential for expression in the endothelium.• RNA splicing may play a role in mediating endothelial cell heterogeneity.We previously demonstrated that the first intron of the human von Willebrand factor (vWF) is required for gene expression in the endothelium of transgenic mice. Based on this finding, we hypothesized that RNA splicing plays a role in mediating vWF expression in the vasculature. To address this question, we used transient transfection assays in human endothelial cells and megakaryocytes with intron-containing and intronless human vWF promoter-luciferase constructs. Next, we generated knockin mice in which LacZ was targeted to the endogenous mouse vWF locus in the absence or presence of the native first intron or heterologous introns from the human b-globin, mouse Down syndrome critical region 1, or hagfish coagulation factor X genes. In both the in vitro assays and the knockin mice, the loss of the first intron of vWF resulted in a significant reduction of reporter gene expression in endothelial cells but not megakaryocytes. This effect was rescued to varying degrees by the introduction of a heterologous intron. Intron-mediated enhancement of expression was mediated at a posttranscriptional level. Together, these findings implicate a role for intronic splicing in mediating lineage-specific expression of vWF in the endothelium. (Blood. 2013;121(21):4404-4412) Introduction Von Willebrand factor (vWF) is a plasma protein that mediates platelet hemostatic function and stabilizes coagulation factor VIII. vWF plays a particularly important role in platelet adhesion and aggregation at sites of high shear rates.1 Expression of vWF is restricted to endothelial cells and platelets. vWF is differentially expressed in the vasculature. For example, vWF protein and mRNA levels are higher in veins, compared with arteries, 2,3 and in venules compared with arterioles. 4 Within the microvasculature, vWF is expressed at particularly low levels in the liver. Expression of vWF also varies between neighboring endothelial cells. 5 The elucidation of the mechanisms underlying vWF expression may provide important insights into the molecular basis of vascular diversity.The structural organization of the mouse, human, and bovine vWF promoter-proximal region is closely related. [6][7][8] The first exon (11 to 1 246 in human vWF) encodes the 59 untranslated sequence. The second exon contains the ATG translational start site. Exons 1 and 2 are separated by an intron (1247 to 11475 in human vWF). To study mechanisms of vWF gene regulation, we have previously used a plug-insocket approach in which a single copy of a vWF promoter-LacZ cassette is targeted to the Hprt locus of mice. Using this strategy, we showed that a region of the human vWF gene (termed vWF2, between 22182 and the end of the first intron) directed expression in the vasculature of the brain, heart and skeletal muscle, but not in other organs such as aorta, lung, liver, spleen, ...

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The Cathepsin L First Intron Stimulates Gene Expression in Rat Sertoli Cells1

Cited by 21 publications

References 62 publications

Tandem repeat variation in human and great ape populations and its impact on gene expression divergence

Tandem repeat variation in human and great ape populations and its impact on gene expression divergence

Role for gene looping in intron-mediated enhancement of transcription

Role of RNA splicing in mediating lineage-specific expression of the von Willebrand factor gene in the endothelium

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