Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease

Tufarelli, Cristina; Stanley, Jackie A Sloane; Garrick, David; Sharpe, Jacqueline A.; Ayyub, Helena; Wood, W. G.; Higgs, Douglas R.

doi:10.1038/ng1157

Cited by 493 publications

(368 citation statements)

References 36 publications

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“…Second, antisense mRNAs were suggested to promote the methylation of sense mRNA promoters. And third, the formation of double-stranded RNA hybrids may interfere with further mRNA processing (Wutz et al, 1997;Lai, 2002;Prescott and Proudfoot, 2002;Tufarelli et al, 2003;Lavorgna et al, 2004;Crampton et al, 2006). These models are not mutually exclusive, and more than one of them may apply to the situation of p53 and WRAP53.…”

Section: Discussionmentioning

confidence: 99%

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

Bug

Dobbelstein

2011

Oncogene

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Mutant p53 frequently accumulates in cancer cells and promotes tumor cell invasion, as part of its gain of function. Its accumulation is partially due to enhanced stability, but little is known about how the mRNA levels of mutant p53 can be regulated. Likewise, the impact of cancer therapy on the levels of mutant p53 is poorly understood. We show here that the anthracyclines doxorubicin, daunorubicin and epirubicin further increase the amounts of mutant p53 mRNA and protein in cancer cells. Moreover, we show for the first time that the transcription factor E2F1 associates with the promoter DNA of TP53. Upon genotoxic treatment, E2F1 contributed to the expression of mutant p53, both directly and through induction of TAp73. In contrast, the anthracycline idarubicin and also another topoisomerase inhibitor, etoposide, failed to increase the levels of p53 mRNA, despite their ability to induce the synthesis of TAp73 mRNA. Instead, a natural antisense transcript of TP53, WRAP53, was strongly augmented by idarubicin and etoposide, but only less so by the other anthracyclines under study. RNA corresponding to the first exon of WRAP53 was mainly found in cell nuclei and it reduced the levels of mutant p53. Taken together, this suggests a reciprocal activation pattern of TP53 and WRAP53 by different chemotherapeutics. Reducing the levels of mutant p53 by small-interfering RNA increased chemosensitivity, and idarubicin prevented cell survival more efficiently than the mutant p53-inducing doxorubicin. We conclude that even closely related anthracyclines induce the synthesis of different, opposing transcripts from the TP53 locus. When using these drugs for cancer therapy, the increased levels of mutant p53 may augment its gain of function and thus favor unwanted chemoresistance and tumor progression.

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Section: Discussionmentioning

confidence: 99%

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

Bug

Dobbelstein

2011

Oncogene

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“…To date, antisense transcripts have been observed for up to 75% of the mammalian transcriptome in data sets generated by both sequence-based and hybridization-based methods (Katayama et al 2005). Given the high prevalence of antisense transcription in the mammalian genome, and the link between antisense transcripts and disease (Tufarelli et al 2003;Reis et al 2004), Tag-seq was well suited to the study of cancer-relevant gene expression in the context of the CGAP project. We found known and novel S-AS gene pairs for which the ratio of expression changed significantly between The enrichment of miRNA targeting sites increased further for those genes with differential expression values in the top 20% and even further for those in the top 10%.…”

Section: Discussionmentioning

confidence: 99%

“…We first analyzed the AS tags with a focus on their differential expression in libraries representing cancerous and normal tissue samples. Previous studies have shown that the ratio of sense to antisense transcripts changes between normal and malignant tissue samples , and that antisense transcripts can be implicated in disease processes (Tufarelli et al 2003;Reis et al 2004). Our goal was to highlight the potential of the Tag-seq approach to identify known and novel antisense transcripts whose expression ratios changed significantly with respect to the sense gene, between normal and diseased states, between different stages of disease progression, or between cancer subtypes.…”

Section: Sense-antisense Transcripts In Cancer Librariesmentioning

confidence: 99%

Next-generation tag sequencing for cancer gene expression profiling

Morrissy¹,

Morin²,

Delaney³

et al. 2009

Genome Res.

295

259

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We describe a new method, Tag-seq, which employs ultra high-throughput sequencing of 21 base pair cDNA tags for sensitive and cost-effective gene expression profiling. We compared Tag-seq data to LongSAGE data and observed improved representation of several classes of rare transcripts, including transcription factors, antisense transcripts, and intronic sequences, the latter possibly representing novel exons or genes. We observed increases in the diversity, abundance, and dynamic range of such rare transcripts and took advantage of the greater dynamic range of expression to identify, in cancers and normal libraries, altered expression ratios of alternative transcript isoforms. The strand-specific information of Tag-seq reads further allowed us to detect altered expression ratios of sense and antisense (S-AS) transcripts between cancer and normal libraries. S-AS transcripts were enriched in known cancer genes, while transcript isoforms were enriched in miRNA targeting sites. We found that transcript abundance had a stronger GC-bias in LongSAGE than Tagseq, such that AT-rich tags were less abundant than GC-rich tags in LongSAGE. Tag-seq also performed better in gene discovery, identifying >98% of genes detected by LongSAGE and profiling a distinct subset of the transcriptome characterized by AT-rich genes, which was expressed at levels below those detectable by LongSAGE. Overall, Tag-seq is sensitive to rare transcripts, has less sequence composition bias relative to LongSAGE, and allows differential expression analysis for a greater range of transcripts, including transcripts encoding important regulatory molecules.

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“…La même équipe de D.R. Higgs a donc poussé l'exploration de sa première publication afin de confirmer le diagnostic [8]. En précisant les limites de la délétion, on constate qu'elle ampute l'extrémité 3' du gène LUC7L, dont les trois derniers exons et la zone de polyadénylation sont délétés (Figure 1).…”

Section: Nouvelleunclassified

Une nouvelle cause de maladie génétique: l’inactivation d’un gène par un transcrit d’ARN antisens

Labie

2004

Med Sci (Paris)

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Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease

Cited by 493 publications

References 36 publications

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

Next-generation tag sequencing for cancer gene expression profiling

Une nouvelle cause de maladie génétique: l’inactivation d’un gène par un transcrit d’ARN antisens

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