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Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis.

Fan J, Xing Y, Wen X, Jia R, Ni H, He J, Ding X, Pan H, Qian G, Ge S, Hoffman AR, Zhang H, Fan X - Genome Biol. (2015)

Bottom Line: Suppression of ROR in tumors results in silencing of TESC expression, and G9A-mediated histone H3K9 methylation in the TESC promoter is restored, which significantly reduces tumor growth and metastasis.Without ROR silencing, TESC knockdown presents consistent and significant reductions in tumor progression.Our results reveal a novel mechanism by which ROR may serve as a decoy oncoRNA that blocks binding surfaces, preventing the recruitment of histone modifying enzymes, thereby specifying a new pattern of histone modifications that promote tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, P. R. China.

ABSTRACT

Background: Long non-coding RNAs (lncRNAs) are not translated into proteins and were initially considered to be part of the 'dark matter' of the genome. Recently, it has been shown that lncRNAs play a role in the recruitment of chromatin modifying complexes and can influence gene expression. However, it is unknown if lncRNAs function in a similar way in cancer.

Results: Here, we show that the lncRNA ROR occupies and activates the TESC promoter by repelling the histone G9A methyltransferase and promoting the release of histone H3K9 methylation. Suppression of ROR in tumors results in silencing of TESC expression, and G9A-mediated histone H3K9 methylation in the TESC promoter is restored, which significantly reduces tumor growth and metastasis. Without ROR silencing, TESC knockdown presents consistent and significant reductions in tumor progression.

Conclusions: Our results reveal a novel mechanism by which ROR may serve as a decoy oncoRNA that blocks binding surfaces, preventing the recruitment of histone modifying enzymes, thereby specifying a new pattern of histone modifications that promote tumorigenesis.

No MeSH data available.


Related in: MedlinePlus

ROR repels endogenous G9A methyltransferase. a ChIP assay demonstrating that ROR blocked the recruitment of G9A to the TESC promoter. IgG is used as a native control. T1 through T4 and T11 through T12: primer names; arrow: transcriptional direction; sites X, Y and W: ChIP detecting sites; grey box: exons of TESC genes. b, c The qPCR-ChIP assay showing the interaction of G9A with the TESC promoter. The detection of ChIP sites on the chromosome is listed at the bottom. IgG: native control. All of the data are presented as the mean ± SD. *P <0.05: compared with the control and mock. d Decoy model of ROR regulation in tumorigenesis. In normal cells, ROR lncRNA was silenced and the G9A methyltransferase could freely modify the TESC promoter and provide histone H3K9 methylation to depress TESC expression; however, in cancer cells, ROR was abnormally activated and blocked the G9A interaction with the TESC promoter, and free G9A failed to methylate the TESC promoter and induced aberrant TESC expression, triggering tumorigenesis
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Fig7: ROR repels endogenous G9A methyltransferase. a ChIP assay demonstrating that ROR blocked the recruitment of G9A to the TESC promoter. IgG is used as a native control. T1 through T4 and T11 through T12: primer names; arrow: transcriptional direction; sites X, Y and W: ChIP detecting sites; grey box: exons of TESC genes. b, c The qPCR-ChIP assay showing the interaction of G9A with the TESC promoter. The detection of ChIP sites on the chromosome is listed at the bottom. IgG: native control. All of the data are presented as the mean ± SD. *P <0.05: compared with the control and mock. d Decoy model of ROR regulation in tumorigenesis. In normal cells, ROR lncRNA was silenced and the G9A methyltransferase could freely modify the TESC promoter and provide histone H3K9 methylation to depress TESC expression; however, in cancer cells, ROR was abnormally activated and blocked the G9A interaction with the TESC promoter, and free G9A failed to methylate the TESC promoter and induced aberrant TESC expression, triggering tumorigenesis

Mentions: To determine whether ROR abolished G9A binding at the TESC promoter in the cell nucleus, we used a ChIP assay and showed that ROR blocked the recruitment of G9A to the TESC promoter (Fig. 7a, lane 13, 16) in the two controls (mock and non-treatment cells); however, with ROR silencing, G9A could dramatically bind to the TESC promoter nearby (Fig. 7a, lane 14, 17). We used two negative ChIP sites (X and W) to exclude a non-specific interaction. As expected, G9A binding was not measured with the TESC promoter regardless of the ROR expression status at these native sites.Fig. 7


Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis.

Fan J, Xing Y, Wen X, Jia R, Ni H, He J, Ding X, Pan H, Qian G, Ge S, Hoffman AR, Zhang H, Fan X - Genome Biol. (2015)

ROR repels endogenous G9A methyltransferase. a ChIP assay demonstrating that ROR blocked the recruitment of G9A to the TESC promoter. IgG is used as a native control. T1 through T4 and T11 through T12: primer names; arrow: transcriptional direction; sites X, Y and W: ChIP detecting sites; grey box: exons of TESC genes. b, c The qPCR-ChIP assay showing the interaction of G9A with the TESC promoter. The detection of ChIP sites on the chromosome is listed at the bottom. IgG: native control. All of the data are presented as the mean ± SD. *P <0.05: compared with the control and mock. d Decoy model of ROR regulation in tumorigenesis. In normal cells, ROR lncRNA was silenced and the G9A methyltransferase could freely modify the TESC promoter and provide histone H3K9 methylation to depress TESC expression; however, in cancer cells, ROR was abnormally activated and blocked the G9A interaction with the TESC promoter, and free G9A failed to methylate the TESC promoter and induced aberrant TESC expression, triggering tumorigenesis
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4499915&req=5

Fig7: ROR repels endogenous G9A methyltransferase. a ChIP assay demonstrating that ROR blocked the recruitment of G9A to the TESC promoter. IgG is used as a native control. T1 through T4 and T11 through T12: primer names; arrow: transcriptional direction; sites X, Y and W: ChIP detecting sites; grey box: exons of TESC genes. b, c The qPCR-ChIP assay showing the interaction of G9A with the TESC promoter. The detection of ChIP sites on the chromosome is listed at the bottom. IgG: native control. All of the data are presented as the mean ± SD. *P <0.05: compared with the control and mock. d Decoy model of ROR regulation in tumorigenesis. In normal cells, ROR lncRNA was silenced and the G9A methyltransferase could freely modify the TESC promoter and provide histone H3K9 methylation to depress TESC expression; however, in cancer cells, ROR was abnormally activated and blocked the G9A interaction with the TESC promoter, and free G9A failed to methylate the TESC promoter and induced aberrant TESC expression, triggering tumorigenesis
Mentions: To determine whether ROR abolished G9A binding at the TESC promoter in the cell nucleus, we used a ChIP assay and showed that ROR blocked the recruitment of G9A to the TESC promoter (Fig. 7a, lane 13, 16) in the two controls (mock and non-treatment cells); however, with ROR silencing, G9A could dramatically bind to the TESC promoter nearby (Fig. 7a, lane 14, 17). We used two negative ChIP sites (X and W) to exclude a non-specific interaction. As expected, G9A binding was not measured with the TESC promoter regardless of the ROR expression status at these native sites.Fig. 7

Bottom Line: Suppression of ROR in tumors results in silencing of TESC expression, and G9A-mediated histone H3K9 methylation in the TESC promoter is restored, which significantly reduces tumor growth and metastasis.Without ROR silencing, TESC knockdown presents consistent and significant reductions in tumor progression.Our results reveal a novel mechanism by which ROR may serve as a decoy oncoRNA that blocks binding surfaces, preventing the recruitment of histone modifying enzymes, thereby specifying a new pattern of histone modifications that promote tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, P. R. China.

ABSTRACT

Background: Long non-coding RNAs (lncRNAs) are not translated into proteins and were initially considered to be part of the 'dark matter' of the genome. Recently, it has been shown that lncRNAs play a role in the recruitment of chromatin modifying complexes and can influence gene expression. However, it is unknown if lncRNAs function in a similar way in cancer.

Results: Here, we show that the lncRNA ROR occupies and activates the TESC promoter by repelling the histone G9A methyltransferase and promoting the release of histone H3K9 methylation. Suppression of ROR in tumors results in silencing of TESC expression, and G9A-mediated histone H3K9 methylation in the TESC promoter is restored, which significantly reduces tumor growth and metastasis. Without ROR silencing, TESC knockdown presents consistent and significant reductions in tumor progression.

Conclusions: Our results reveal a novel mechanism by which ROR may serve as a decoy oncoRNA that blocks binding surfaces, preventing the recruitment of histone modifying enzymes, thereby specifying a new pattern of histone modifications that promote tumorigenesis.

No MeSH data available.


Related in: MedlinePlus