Several Liver-Specific DNase Hypersensitive Sites Are Present in the Intergenic Region Separating Human Plasminogen and Apoprotein(A) Genes

Magnaghi, Paola; Mihalich, Alessandra; Taramelli, Roberto

doi:10.1006/bbrc.1994.2754

Cited by 18 publications

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“…1 and 2). It coincides with one of the four liverspecific DNase I hypersensitive sites, DH III, reported by Magnaghi et al (37). This 1.8-kb fragment is capable of enhancing apo(a) transcription in an orientation-independent manner and was therefore studied in detail.…”

Section: Identification Of An Apo(a) Gene Transcription Enhancer-supporting

confidence: 79%

Apolipoprotein(a) Gene Enhancer Resides within a LINE Element

Yang

Boffelli

Boonmark

et al. 1998

Journal of Biological Chemistry

111

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Apolipoprotein(a), (apo(a)), is the distinguishing protein portion of the lipoprotein(a) particle, elevated plasma levels of which are a major risk factor for cardiovascular disease. A search for enhancer elements that control the transcription of the apo(a) gene led to the identification of an upstream element that contains target binding sites for members of the Ets and Sp1 nuclear protein families. The enhancer element functions in either orientation to confer a greater than 10-fold increase in the activity of the apo(a) minimal promoter in cultured hepatocyte cells. Unexpectedly, the enhancer element is located within a LINE retrotransposon element, suggesting that LINE elements may function as mobile regulatory elements to control the expression of nearby genes.

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Section: Identification Of An Apo(a) Gene Transcription Enhancer-supporting

confidence: 79%

Apolipoprotein(a) Gene Enhancer Resides within a LINE Element

Yang

Boffelli

Boonmark

et al. 1998

Journal of Biological Chemistry

111

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“…Likewise a common cis-acting regulatory domain seems to mediate the hepatic expression of the clustered apoprotein E and CI genes [47]. We are presently in the process of assessing, in HepG2 cells and in transgenic animals, whether the -2 kb plasminogen enhancer is acting in synergism with the apoprotein(a) HNF-1 site, b y analyzing larger segments that include the entire intergenic region between plasminogen and apoprotein(a) [50].…”

Section: Discussionmentioning

confidence: 99%

Motifs Resembling Hepatocyte Nuclear Factor 1 and Activator Protein 3 Mediate the Tissue Specificity of the Human Plasminogen Gene

Meroni

Buraggi

Mantovani

et al. 1996

European Journal of Biochemistry

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Plasminogen is one of the key elements in the fibrinolytic process. Like most of the gene products that participate in such reactions and which interact with plasminogen, the site of its synthesis is mainly confined to the hepatocyte. Plasminogen RNA has additionally been detected in kidney and very low amounts also in testes. Deletional analysis has indicated that two 5' sequences located within 2.5 kb of the first ATG are responsible for the transcriptional activation and the tissue specificity of the expression of the gene. By DNase protection and gel mobility shift assays with HepG2 nuclear extracts, the two sequences were localized and found to be the recognition sites for the widely known hepatocyte nuclear factor 1 (HNF-1) a trans-acting factor, and a nuclear factor like activator protein 3 (AP-3). The first one lies in a rather unusual position, i.e. within the 5'-untranslated region. The latter is located further upstream in a region between -2200 and -2100 from the plasminogen mRNA cap site. Moreover, sitedirected mutagenesis coupled by functional experiments in HepG2 cells has demonstrated a synergism between these two positively acting elements in controlling the transcription of the human plasminogen gene.Keywords: plasminogen; apoprotein(a) ; gene cluster; promoter; trans-acting factors.Plasminogen is a zymogen synthesized in the liver which is involved in the final step of fibrinolysis. During this process plasminogen is converted to plasmin following the action of a number of activators, including tissue plasminogen activator and urokinase [l]. The one-chain proenzyme is converted to a twochain active plasmin molecule by cleavage of a specific internal peptide bond between Arg560 and Val562 [2]. The carboxy portion of the protein contains the serine protease function of the molecule which shows a remarkable degree of homology with the serine proteases involved in blood coagulation and other physiological processes [3]. On the other hand, in the aminoterminal region there are five tandem repeats called kringles (1 -5) and a leader sequence [3, 41. Kringle modules, which are also present in several members of the serine protease superfamily, are protein binding domains important for the specificity, function and regulation of these proteins [3].An impressive sequence similarity with plasminogen, both at the protein and DNA levels, has been discovered with the cloning of the cDNA coding for apoprotein(a) [5]. Apoprotein(a), like plasminogen, comprises a 5' signal peptide, multiple repeats of a kringle-IV-like motif, followed by a single kringle-V-like domain and a protease module [5J. Recent YAC cloning has revealed that the genes coding for plasminogen and apolipoprotein(a) are separated by 40 kb of genomic DNA on the telomeric region of chromosome 6 (6q26) and are organized in a head-to-head configuration [6-91. Moreover, the same YAC cloning approach has also uncovered the presence of two otherCorrespondence to

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“…Recent findings have also suggested that elements that lie outside the 5Ј region of the apo(a) gene may also be required for its expression. 14 The ACR region colocalizes with a DNase I-hypersensitive site that was initially identified exclusively in hepatoma cell types in vitro 32 and in vivo in the liver of apo(a)-YAC transgenic mice. 18 Although these observations may indicate that the ACR acts as a hepatic control region of apo(a) expression, in vitro the enhancer does not exhibit tissue specificity.…”

Section: Huby Et Al In Vivo Analysis Of a Distal Apo(a) Enhancer 1637mentioning

confidence: 99%

“…17,18 We cannot exclude, however, the possibility that integration site-specific silencing effects may have dampened the ACR activity or that the presence of other functional LCR activities contribute along with the ACR element to general transcriptional activation at the apo(a) genomic locus. Notably, in the 40-kb intergenic region that separates the 5Ј regions of the apo(a) and plasminogen genes, 3 other DNase I-hypersensitive sites are present, 32 including the apo(a) enhancer DHII 19 ; these regions represent important candidate regions. Recent findings have also suggested that elements that lie outside the 5Ј region of the apo(a) gene may also be required for its expression.…”

Section: Huby Et Al In Vivo Analysis Of a Distal Apo(a) Enhancer 1637mentioning

confidence: 99%

Regulation of the Expression of the Apolipoprotein(a) Gene

Huby

Afzal

Doucet

et al. 2003

ATVB

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Objective-The apolipoprotein(a) [apo(a)] gene locus is the major determinant of the circulating concentration of the atherothrombogenic lipoprotein Lp(a). In vitro analysis of the intergenic region between the apo(a) and plasminogen genes revealed the presence of a putative apo(a) transcription control region (ACR) approximately 20 kb upstream of the apo(a) gene that significantly increases the minimal promoter activity of the human apo(a) gene. Methods and Results-To examine the function of the ACR in its natural genomic context, we used the Cre-loxP recombination system to generate 2 nearly identical apo(a)-yeast artificial chromosome transgenic mouse lines that possess a single integration site for the human apo(a) transgene in the mouse genome but differ by the presence or absence of the ACR enhancer. Analysis of the 2 groups of animals revealed that the deletion of the ACR was associated with 30% reduction in plasma and mRNA apo(a) levels. Apo(a)-yeast artificial chromosome transgenic mice with and without the ACR sequence were similar in all other aspects of apo(a) regulation, including liver-specific apo(a) expression and alteration in expression levels in response to sexual maturation and a high-fat diet. ] is a cholesterol-rich particle that differs from LDL by the presence of the highly glycosylated apolipoprotein (apo) apo(a), which is covalently linked by a disulfide bond to apoB100. 1,2 Clinical interest in Lp(a) lies in its potential role as a proatherogenic and prothrombogenic risk factor. 3 Despite some conflicting results, numerous prospective studies have demonstrated an association between elevated levels of Lp(a) and coronary heart disease. 4 The plasma concentration of Lp(a) is an inherited quantitative trait and remains fairly constant throughout life in a given individual. Nevertheless, Lp(a) levels may differ over a thousand-fold range between individuals. The apo(a) gene is the major determinant of lipoprotein(a) concentration. It has been estimated that the apo(a) gene locus explain from 74% to more than 90% of the intraindividual variability in Lp(a) levels in the white population. 5,6 The size polymorphism of apo(a) affects apo(a) protein processing 7 and clearly accounts for a significant portion of the total variability in Lp(a) levels seen in human populations. 5,8,9 However, other cis-sequences that influence apo(a) expression are also believed to contribute to variance in plasma Lp(a) levels. 10 -12 In addition to humans, the apo(a) gene is naturally present only in Old World monkeys and the hedgehog. Because of the paucity of model organisms with an apo(a) orthologue, the regulation of apo(a) synthesis has been difficult to assess in vivo. Yeast artificial chromosome (YAC) genomic clones carrying human apo(a) alleles with significant 5Ј and 3Ј human flanking DNA have been used to generate transgenic mouse lines. 13,14 These transgenic mice, expressing apo(a) in an appropriate liver-specific manner, have provided information regarding the regulation of apo(a) mRNA synthesi...

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Several Liver-Specific DNase Hypersensitive Sites Are Present in the Intergenic Region Separating Human Plasminogen and Apoprotein(A) Genes

Cited by 18 publications

References 0 publications

Apolipoprotein(a) Gene Enhancer Resides within a LINE Element

Apolipoprotein(a) Gene Enhancer Resides within a LINE Element

Motifs Resembling Hepatocyte Nuclear Factor 1 and Activator Protein 3 Mediate the Tissue Specificity of the Human Plasminogen Gene

Regulation of the Expression of the Apolipoprotein(a) Gene

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