HERV-E-Mediated Modulation of PLA2G4A Transcription in Urothelial Carcinoma

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From: PLoS ONE(Vol. 7, Issue 11)
Publisher: Public Library of Science
Document Type: Article
Length: 10,268 words
Lexile Measure: 1470L

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Author(s): Darko Gosenca 1 , * , Ute Gabriel 2 , Annette Steidler 2 , Jens Mayer 3 , Olivia Diem 4 , Philipp Erben 1 , 2 , Alice Fabarius 1 , Christine Leib-Mösch 1 , 4 , Wolf-Karsten Hofmann 1 , Wolfgang Seifarth 1


Constituting at least 40% of the human genome it is becoming increasingly evident that genetic mobile elements are an integral part of the transcriptional regulatory machinery of the cell and can influence gene expression at transcription and protein levels [1], [2], [3], [4], [5], [6]. Since molecular pathogenesis of all human cancers concurs with alterations in gene and/or gene product activities [7], an involvement of transposable elements (TEs) in carcinogenesis was repeatedly postulated [8], [9], [10]. TE activities in human cancers may reflect pathogenic alterations in disease development or may even actively contribute to pathogenesis by dysregulation of gene expression [11], [12]. Human TEs have been considered to contribute tens of thousands of natural antisense transcripts to human genes [13]. Therefore, their role in regulatory mechanisms such as RNA interference (RNAi) and epigenetics needs to be investigated in both healthy and malignant cells.

LTR retrotransposons including human endogenous retroviruses (HERVs) constitute about one fifth of human TEs and 8-9% of the human genome. Contributing a high number of promoters to gene regulatory networks they have a long history not only as potential pathogens but also as a source of genetic variation, genome evolution, and gene regulation [1], [3], [13], reviewed in [4], [6], [14], [15], [16]. Whereas some LTR elements such as mammalian apparent LTR retrotransposons (MaLR) represent ancient retrotransposons, class I, II and III HERVs are considered to be remnants of germ line infections by exogenous retroviruses that were endogenized and genetically fixed in the human population [17], [18], [19] (reviewed in [14]). In the course of evolution endogenous retroviruses have been amplified several times and thus spread throughout the genome by repeated events of retrotransposition and/or reinfection [20].

Although HERVs are noninfectious, replication-defective retroviral relics, at least some proviruses of each HERV group were found to be still transcriptionally active [21]. In addition, many solitary HERV LTRs, remnants of internal recombination events, have preserved their promoter activity and still contain active regulatory elements such as enhancer sequences, transcription factor binding sites or polyadenylation signals [4], [22], [23]. A bioinformatical analysis revealed tens of thousands of active retroviral promoters in the human genome [2]. According to this approach transcribed HERV sequences were derived from 1.16% of the human genome and all transcripts that initiate from LTRs were found to cover 22.4% of the human genome sequence. Moreover, HERV-LTR-initiated antisense transcripts may modulate the corresponding sense transcript levels and thus influence gene expression [24]. In some cases, HERVs have adopted physiological "symbiotic" functions (reviewed in [6], [25], [26]).The probably most prominent example of HERV importance for physiological functions is the expression of Env proteins (Syncytin1 and 2) in the placenta that play an essential role in cell-fusion during syncytiotrophoblast formation [27] and maternofetal...

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Gale Document Number: GALE|A477091695