Abstract
Widespread mRNA 3′ UTR shortening through alternative polyadenylation1 promotes tumor growth in vivo2. 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 gene3 involved in ceRNA crosstalk4 with nine 3′UTR-shortening genes, including EPS15 and NFIA. Knockdown of NUDT21, a master 3′ UTR-shortening regulator2, 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) | 1-7 |
| Number of pages | 7 |
| Journal | Nature Genetics |
| DOIs | |
| State | Accepted/In press - May 21 2018 |
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ASJC Scopus subject areas
- Genetics
Cite this
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; Li, Wei.
In: Nature Genetics, 21.05.2018, p. 1-7.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 3′ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk
AU - Park, Hyun Jung
AU - Ji, Ping
AU - Kim, Soyeon
AU - Xia, Zheng
AU - Rodriguez, Benjamin
AU - Li, Lei
AU - Su, Jianzhong
AU - Chen, Kaifu
AU - Masamha, Chioniso P.
AU - Baillat, David
AU - Fontes-Garfias, Camila R.
AU - Shyu, Ann Bin
AU - Neilson, Joel R.
AU - Wagner, Eric
AU - Li, Wei
PY - 2018/5/21
Y1 - 2018/5/21
N2 - Widespread mRNA 3′ UTR shortening through alternative polyadenylation1 promotes tumor growth in vivo2. 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 gene3 involved in ceRNA crosstalk4 with nine 3′UTR-shortening genes, including EPS15 and NFIA. Knockdown of NUDT21, a master 3′ UTR-shortening regulator2, 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.
AB - Widespread mRNA 3′ UTR shortening through alternative polyadenylation1 promotes tumor growth in vivo2. 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 gene3 involved in ceRNA crosstalk4 with nine 3′UTR-shortening genes, including EPS15 and NFIA. Knockdown of NUDT21, a master 3′ UTR-shortening regulator2, 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.
UR - http://www.scopus.com/inward/record.url?scp=85047190754&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047190754&partnerID=8YFLogxK
U2 - 10.1038/s41588-018-0118-8
DO - 10.1038/s41588-018-0118-8
M3 - Article
C2 - 29785014
AN - SCOPUS:85047190754
SP - 1
EP - 7
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
ER -