3′ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk

Hyun Jung Park; Ping Ji; Soyeon Kim; Zheng Xia; Benjamin Rodriguez; Lei Li; Jianzhong Su; Kaifu Chen; Chioniso P. Masamha; David Baillat; Camila R. Fontes-Garfias; Ann Bin Shyu; Joel R. Neilson; Eric J. Wagner; Wei Li

doi:10.1038/s41588-018-0118-8

3′ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk

Hyun Jung Park, Ping Ji, Soyeon Kim, Zheng Xia, Benjamin Rodriguez, Lei Li, Jianzhong Su, Kaifu Chen, Chioniso P. Masamha, David Baillat, Camila R. Fontes-Garfias, Ann Bin Shyu, Joel R. Neilson, Eric J. Wagner, Wei Li

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article

35 Scopus citations

Abstract

Widespread mRNA 3′ UTR shortening through alternative polyadenylation ¹ promotes tumor growth in vivo ² . A prevailing hypothesis is that it induces proto-oncogene expression in cis through escaping microRNA-mediated repression. Here we report a surprising enrichment of 3′UTR shortening among transcripts that are predicted to act as competing-endogenous RNAs (ceRNAs) for tumor-suppressor genes. Our model-based analysis of the trans effect of 3′ UTR shortening (MAT3UTR) reveals a significant role in altering ceRNA expression. MAT3UTR predicts many trans-targets of 3′ UTR shortening, including PTEN, a crucial tumor-suppressor gene ³ involved in ceRNA crosstalk ⁴ with nine 3′UTR-shortening genes, including EPS15 and NFIA. Knockdown of NUDT21, a master 3′ UTR-shortening regulator ² , represses tumor-suppressor genes such as PHF6 and LARP1 in trans in a miRNA-dependent manner. Together, the results of our analysis suggest a major role of 3′ UTR shortening in repressing tumor-suppressor genes in trans by disrupting ceRNA crosstalk, rather than inducing proto-oncogenes in cis.

Original language	English (US)
Pages (from-to)	783-789
Number of pages	7
Journal	Nature Genetics
Volume	50
Issue number	6
DOIs	https://doi.org/10.1038/s41588-018-0118-8
State	Published - Jun 1 2018

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ASJC Scopus subject areas

Genetics

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Park, H. J., Ji, P., Kim, S., Xia, Z., Rodriguez, B., Li, L., Su, J., Chen, K., Masamha, C. P., Baillat, D., Fontes-Garfias, C. R., Shyu, A. B., Neilson, J. R., Wagner, E. J., & Li, W. (2018). 3′ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk. Nature Genetics, 50(6), 783-789. https://doi.org/10.1038/s41588-018-0118-8

3′ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk. / Park, Hyun Jung; Ji, Ping; Kim, Soyeon; Xia, Zheng; Rodriguez, Benjamin; Li, Lei; Su, Jianzhong; Chen, Kaifu; Masamha, Chioniso P.; Baillat, David; Fontes-Garfias, Camila R.; Shyu, Ann Bin; Neilson, Joel R.; Wagner, Eric J.; Li, Wei.

In: Nature Genetics, Vol. 50, No. 6, 01.06.2018, p. 783-789.

Research output: Contribution to journal › Article

Park, Hyun Jung ; Ji, Ping ; Kim, Soyeon ; Xia, Zheng ; Rodriguez, Benjamin ; Li, Lei ; Su, Jianzhong ; Chen, Kaifu ; Masamha, Chioniso P. ; Baillat, David ; Fontes-Garfias, Camila R. ; Shyu, Ann Bin ; Neilson, Joel R. ; Wagner, Eric J. ; Li, Wei. / 3′ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk. In: Nature Genetics. 2018 ; Vol. 50, No. 6. pp. 783-789.

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abstract = " Widespread mRNA 3′ UTR shortening through alternative polyadenylation 1 promotes tumor growth in vivo 2 . A prevailing hypothesis is that it induces proto-oncogene expression in cis through escaping microRNA-mediated repression. Here we report a surprising enrichment of 3′UTR shortening among transcripts that are predicted to act as competing-endogenous RNAs (ceRNAs) for tumor-suppressor genes. Our model-based analysis of the trans effect of 3′ UTR shortening (MAT3UTR) reveals a significant role in altering ceRNA expression. MAT3UTR predicts many trans-targets of 3′ UTR shortening, including PTEN, a crucial tumor-suppressor gene 3 involved in ceRNA crosstalk 4 with nine 3′UTR-shortening genes, including EPS15 and NFIA. Knockdown of NUDT21, a master 3′ UTR-shortening regulator 2 , represses tumor-suppressor genes such as PHF6 and LARP1 in trans in a miRNA-dependent manner. Together, the results of our analysis suggest a major role of 3′ UTR shortening in repressing tumor-suppressor genes in trans by disrupting ceRNA crosstalk, rather than inducing proto-oncogenes in cis. ",

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