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

Research output: Contribution to journal › Article › peer-review

137 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
Externally published	Yes

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/s41588-018-0118-8

Cite this

@article{2778b1a3f091495599a782612990c391,

title = "3′ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = jun,

day = "1",

doi = "10.1038/s41588-018-0118-8",

language = "English (US)",

volume = "50",

pages = "783--789",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "6",

}

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 J.

AU - Li, Wei

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85047190754

UR - https://www.scopus.com/pages/publications/85047190754#tab=citedBy

U2 - 10.1038/s41588-018-0118-8

DO - 10.1038/s41588-018-0118-8

M3 - Article

C2 - 29785014

AN - SCOPUS:85047190754

SN - 1061-4036

VL - 50

SP - 783

EP - 789

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this