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Isoform switching and exon skipping induced by the DNA methylation inhibitor 5-Aza-2'-deoxycytidine.
- Source :
-
Scientific reports [Sci Rep] 2016 Apr 19; Vol. 6, pp. 24545. Date of Electronic Publication: 2016 Apr 19. - Publication Year :
- 2016
-
Abstract
- DNA methylation in gene promoters leads to gene silencing and is the therapeutic target of methylation inhibitors such as 5-Aza-2'-deoxycytidine (5-Aza-CdR). By analyzing the time series RNA-seq data (days 5, 9, 13, 17) obtained from human bladder cells exposed to 5-Aza-CdR with 0.1 uM concentration, we showed that 5-Aza-CdR can affect isoform switching and differential exon usage (i.e., exon-skipping), in addition to its effects on gene expression. We identified more than 2,000 genes with significant expression changes after 5-Aza-CdR treatment. Interestingly, 29 exon-skipping events induced by treatment were identified and validated experimentally. Particularly, exon-skipping event in Enhancer of Zeste Homologue 2 (EZH2) along with expression changes showed significant down regulation on Day 5 and Day 9 but returned to normal level on Day 13 and Day 17. EZH2 is a component of the multi-subunit polycomb repressive complex PRC2, and the down-regulation of exon-skipping event may lead to the regain of functional EZH2 which was consistent with our previous finding that demethylation may cause regain of PRC2 in demethylated regions. In summary, our study identified pervasive transcriptome changes of bladder cancer cells after treatment with 5-Aza-CdR, and provided valuable insights into the therapeutic effects of 5-Aza-CdR in current clinical trials.
- Subjects :
- Azacitidine administration & dosage
Cell Line, Tumor
Decitabine
Enhancer of Zeste Homolog 2 Protein genetics
Exons drug effects
Gene Expression Regulation, Neoplastic drug effects
Humans
Promoter Regions, Genetic genetics
Protein Isoforms drug effects
Sequence Analysis, RNA
Urinary Bladder Neoplasms pathology
Azacitidine analogs & derivatives
DNA Methylation genetics
Enhancer of Zeste Homolog 2 Protein biosynthesis
Protein Isoforms genetics
Urinary Bladder Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 6
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 27090213
- Full Text :
- https://doi.org/10.1038/srep24545