LIN28 Binds Messenger RNAs at GGAGA Motifs and Regulates Splicing Factor Abundance

被引：239

作者：

Wilbert, Melissa L. ^{[1
,2
]}

Huelga, Stephanie C. ^{[1
,2
]}

Kapeli, Katannya ^{[1
,2
]}

Stark, Thomas J. ^{[1
,2
]}

Liang, Tiffany Y. ^{[1
,2
]}

Chen, Stella X. ^{[1
,2
]}

Yan, Bernice Y. ^{[1
,2
]}

Nathanson, Jason L. ^{[1
,2
]}

Hutt, Kasey R. ^{[1
,2
]}

Lovci, Michael T. ^{[1
,2
]}

Kazan, Hilal ^{[3
,4
,5
]}

Vu, Anthony Q. ^{[1
,2
]}

Massirer, Katlin B. ^{[1
,2
,6
]}

Morris, Quaid ^{[3
,4
,5
]}

Hoon, Shawn ^{[7
,8
]}

Yeo, Gene W. ^{[1
,2
]}

机构：

[1] Univ Calif San Diego, Dept Cellular & Mol Med, Stem Cell Program, San Diego, CA 92103 USA

[2] Univ Calif San Diego, Inst Genom Med, San Diego, CA 92103 USA

[3] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[4] Univ Toronto, Dept Comp Sci, Toronto, ON, Canada

[5] Univ Toronto, Banting & Best Dept Med Res, Toronto, ON, Canada

[6] Univ Estadual Campinas, Ctr Mol Biol & Genet Engn, Campinas, SP, Brazil

[7] Natl Univ Singapore, Dept Biol Sci, Singapore 117548, Singapore

[8] ASTAR, Mol Engn Lab, Singapore, Singapore

来源：

MOLECULAR CELL | 2012年 / 48卷 / 02期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

GENOME-WIDE ANALYSIS; LET-7; MICRORNAS; LIN-28; PROTEIN; MATURATION; IDENTIFICATION; DETERMINANTS; RECOGNITION; REVEALS; NUCLEAR;

D O I：

10.1016/j.molcel.2012.08.004

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

LIN28 is a conserved RNA-binding protein implicated in pluripotency, reprogramming, and oncogenesis. It was previously shown to act primarily by blocking let-7 microRNA (miRNA) biogenesis, but here we elucidate distinct roles of LIN28 regulation via its direct messenger RNA (mRNA) targets. Through crosslinking and immunoprecipitation coupled with high-throughput sequencing (CLIP-seq) in human embryonic stem cells and somatic cells expressing exogenous LIN28, we have defined discrete LIN28-binding sites in a quarter of human transcripts. These sites revealed that LIN28 binds to GGAGA sequences enriched within loop structures in mRNAs, reminiscent of its interaction with let-7 miRNA precursors. Among LIN28 mRNA targets, we found evidence for LIN28 autoregulation and also direct but differing effects on the protein abundance of splicing regulators in somatic and pluripotent stem cells. Splicing-sensitive microarrays demonstrated that exogenous LIN28 expression causes widespread downstream alternative splicing changes. These findings identify important regulatory functions of LIN28 via direct mRNA interactions.

引用

页码：195 / 206

页数：12

共 53 条

[1]

Localization of the developmental timing regulator Lin28 to mRNP complexes, P-bodies and stress granules [J].