Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Published Online February 21, 2008
Science DOI: 10.1126/science.1154040

Reports

Submitted on December 11, 2007
Accepted on February 14, 2008

Selective Blockade of MicroRNA Processing by Lin-28

Srinivas R. Viswanathan 1, George Q. Daley 2*, Richard I. Gregory 1*

1 Stem Cell Program, Children’s Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA.
2 Stem Cell Program, Children’s Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA.; Division of Pediatric Hematology/Oncology, Children’s Hospital Boston and Dana Farber Cancer Institute; and Howard Hughes Medical Institute, Division of Hematology, Brigham and Women’s Hospital, Boston, MA 02115, USA.

* To whom correspondence should be addressed.
George Q. Daley , E-mail: george.daley{at}childrens.harvard.edu
Richard I. Gregory , E-mail: rgregory{at}enders.tch.harvard.edu

MicroRNAs (miRNAs) play critical roles in development, and dysregulation of miRNA expression has been observed in human malignancies. Recent evidence suggests that the processing of several primary miRNA transcripts (pri-miRNAs) is blocked post-transcriptionally in embryonic stem (ES) cells, embryonal carcinoma (EC) cells, and primary tumors. Here we show that Lin-28, a developmentally regulated RNA-binding protein, selectively blocks the processing of pri-let-7 miRNAs in embryonic cells. Using in vitro and in vivo studies, we demonstrate that Lin-28 is necessary and sufficient for blocking Microprocessor-mediated cleavage of pri-let-7 miRNAs. Our results identify Lin-28 as a negative regulator of miRNA biogenesis and suggest that Lin-28 may play a central role in blocking miRNA-mediated differentiation in stem cells and certain cancers.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Mammalian Ovary from Genesis to Revelation.
M. A. Edson, A. K. Nagaraja, and M. M. Matzuk (2009)
Endocr. Rev. 30, 624-712
   Abstract »    Full Text »    PDF »
The estrogen receptor-{alpha}-induced microRNA signature regulates itself and its transcriptional response.
L. Castellano, G. Giamas, J. Jacob, R. C. Coombes, W. Lucchesi, P. Thiruchelvam, G. Barton, L. R. Jiao, R. Wait, J. Waxman, et al. (2009)
PNAS 106, 15732-15737
   Abstract »    Full Text »    PDF »
miR-331-3p Regulates ERBB-2 Expression and Androgen Receptor Signaling in Prostate Cancer.
M. R. Epis, K. M. Giles, A. Barker, T. S. Kendrick, and P. J. Leedman (2009)
J. Biol. Chem. 284, 24696-24704
   Abstract »    Full Text »    PDF »
Loss of Cardiac microRNA-Mediated Regulation Leads to Dilated Cardiomyopathy and Heart Failure.
P. K. Rao, Y. Toyama, H. R. Chiang, S. Gupta, M. Bauer, R. Medvid, F. Reinhardt, R. Liao, M. Krieger, R. Jaenisch, et al. (2009)
Circ. Res. 105, 585-594
   Abstract »    Full Text »    PDF »
SNPs in human miRNA genes affect biogenesis and function.
G. Sun, J. Yan, K. Noltner, J. Feng, H. Li, D. A. Sarkis, S. S. Sommer, and J. J. Rossi (2009)
RNA 15, 1640-1651
   Abstract »    Full Text »    PDF »
LPS induces KH-type splicing regulatory protein-dependent processing of microRNA-155 precursors in macrophages.
T. Ruggiero, M. Trabucchi, F. De Santa, S. Zupo, B. D. Harfe, M. T. McManus, M. G. Rosenfeld, P. Briata, and R. Gherzi (2009)
FASEB J 23, 2898-2908
   Abstract »    Full Text »    PDF »
Cold Shock Domain Protein 3 Regulates Freezing Tolerance in Arabidopsis thaliana.
M.-H. Kim, K. Sasaki, and R. Imai (2009)
J. Biol. Chem. 284, 23454-23460
   Abstract »    Full Text »    PDF »
miRNA Regulation Through Ligand Occupancy of a Nuclear Hormone Receptor.
A. E. Rougvie (2009)
Science Signaling 2, pe52
   Abstract »    Full Text »    PDF »
Estradiol-regulated microRNAs control estradiol response in breast cancer cells.
P. Bhat-Nakshatri, G. Wang, N. R. Collins, M. J. Thomson, T. R. Geistlinger, J. S. Carroll, M. Brown, S. Hammond, E. F. Srour, Y. Liu, et al. (2009)
Nucleic Acids Res. 37, 4850-4861
   Abstract »    Full Text »    PDF »
High-resolution profiling and discovery of planarian small RNAs.
M. R. Friedlander, C. Adamidi, T. Han, S. Lebedeva, T. A. Isenbarger, M. Hirst, M. Marra, C. Nusbaum, W. L. Lee, J. C. Jenkin, et al. (2009)
PNAS 106, 11546-11551
   Abstract »    Full Text »    PDF »
The NF90-NF45 Complex Functions as a Negative Regulator in the MicroRNA Processing Pathway.
S. Sakamoto, K. Aoki, T. Higuchi, H. Todaka, K. Morisawa, N. Tamaki, E. Hatano, A. Fukushima, T. Taniguchi, and Y. Agata (2009)
Mol. Cell. Biol. 29, 3754-3769
   Abstract »    Full Text »    PDF »
Histone H2a mRNA interacts with Lin28 and contains a Lin28-dependent posttranscriptional regulatory element.
B. Xu and Y. Huang (2009)
Nucleic Acids Res. 37, 4256-4263
   Abstract »    Full Text »    PDF »
Post-transcriptional control of DGCR8 expression by the Microprocessor.
R. Triboulet, H.-M. Chang, R. J. LaPierre, and R. I. Gregory (2009)
RNA 15, 1005-1011
   Abstract »    Full Text »    PDF »
Cellular reprogramming and pluripotency induction.
M. W. Lensch (2009)
Br. Med. Bull. 90, 19-35
   Abstract »    Full Text »    PDF »
Cell-cell contact globally activates microRNA biogenesis.
H.-W. Hwang, E. A. Wentzel, and J. T. Mendell (2009)
PNAS 106, 7016-7021
   Abstract »    Full Text »    PDF »
Downregulation of MiR-199a Derepresses Hypoxia-Inducible Factor-1{alpha} and Sirtuin 1 and Recapitulates Hypoxia Preconditioning in Cardiac Myocytes.
S. Rane, M. He, D. Sayed, H. Vashistha, A. Malhotra, J. Sadoshima, D. E. Vatner, S. F. Vatner, and M. Abdellatif (2009)
Circ. Res. 104, 879-886
   Abstract »    Full Text »    PDF »
2'-O-methylation stabilizes Piwi-associated small RNAs and ensures DNA elimination in Tetrahymena.
H. M. Kurth and K. Mochizuki (2009)
RNA 15, 675-685
   Abstract »    Full Text »    PDF »
Small RNA Silencing Pathways in Germ and Stem Cells.
A.A. Aravin and G.J. Hannon (2009)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation.
T.-C. Chang, L. R. Zeitels, H.-W. Hwang, R. R. Chivukula, E. A. Wentzel, M. Dews, J. Jung, P. Gao, C. V. Dang, M. A. Beer, et al. (2009)
PNAS 106, 3384-3389
   Abstract »    Full Text »    PDF »
Lin28 modulates cell growth and associates with a subset of cell cycle regulator mRNAs in mouse embryonic stem cells.
B. Xu, K. Zhang, and Y. Huang (2009)
RNA 15, 357-361
   Abstract »    Full Text »    PDF »
Pattern formation via small RNA mobility.
D. H. Chitwood, F. T.S. Nogueira, M. D. Howell, T. A. Montgomery, J. C. Carrington, and M. C.P. Timmermans (2009)
Genes & Dev. 23, 549-554
   Abstract »    Full Text »    PDF »
Epigenetic reprogramming and induced pluripotency.
K. Hochedlinger and K. Plath (2009)
Development 136, 509-523
   Abstract »    Full Text »    PDF »
Common Themes of Dedifferentiation in Somatic Cell Reprogramming and Cancer.
G.Q. Daley (2009)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
Genome-scale spatiotemporal analysis of Caenorhabditis elegans microRNA promoter activity.
N. J. Martinez, M. C. Ow, J. S. Reece-Hoyes, M. I. Barrasa, V. R. Ambros, and A. J.M. Walhout (2008)
Genome Res. 18, 2005-2015
   Abstract »    Full Text »    PDF »
A SNP in a let-7 microRNA Complementary Site in the KRAS 3' Untranslated Region Increases Non-Small Cell Lung Cancer Risk.
L. J. Chin, E. Ratner, S. Leng, R. Zhai, S. Nallur, I. Babar, R.-U. Muller, E. Straka, L. Su, E. A. Burki, et al. (2008)
Cancer Res. 68, 8535-8540
   Abstract »    Full Text »    PDF »
Identification of specific let-7 microRNA binding complexes in Caenorhabditis elegans.
S.-P. Chan, G. Ramaswamy, E.-Y. Choi, and F. J. Slack (2008)
RNA 14, 2104-2114
   Abstract »    Full Text »    PDF »
An Insect Virus-Encoded MicroRNA Regulates Viral Replication.
M. Hussain, R. J. Taft, and S. Asgari (2008)
J. Virol. 82, 9164-9170
   Abstract »    Full Text »    PDF »
Frequency and fate of microRNA editing in human brain.
Y. Kawahara, M. Megraw, E. Kreider, H. Iizasa, L. Valente, A. G. Hatzigeorgiou, and K. Nishikura (2008)
Nucleic Acids Res. 36, 5270-5280
   Abstract »    Full Text »    PDF »
Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing.
M. A. Newman, J. M. Thomson, and S. M. Hammond (2008)
RNA 14, 1539-1549
   Abstract »    Full Text »    PDF »
Pluripotent stem cell lines.
J. Yu and J. A. Thomson (2008)
Genes & Dev. 22, 1987-1997
   Abstract »    Full Text »    PDF »
Determinants of MicroRNA Processing Inhibition by the Developmentally Regulated RNA-binding Protein Lin28.
E. Piskounova, S. R. Viswanathan, M. Janas, R. J. LaPierre, G. Q. Daley, P. Sliz, and R. I. Gregory (2008)
J. Biol. Chem. 283, 21310-21314
   Abstract »    Full Text »    PDF »
Inducible expression of microRNA-194 is regulated by HNF-1{alpha} during intestinal epithelial cell differentiation.
K. Hino, K. Tsuchiya, T. Fukao, K. Kiga, R. Okamoto, T. Kanai, and M. Watanabe (2008)
RNA 14, 1433-1442
   Abstract »    Full Text »    PDF »
Drosophila let-7 microRNA is required for remodeling of the neuromusculature during metamorphosis.
N. S. Sokol, P. Xu, Y.-N. Jan, and V. Ambros (2008)
Genes & Dev. 22, 1591-1596
   Abstract »    Full Text »    PDF »
The Eukaryotic Genome as an RNA Machine.
P. P. Amaral, M. E. Dinger, T. R. Mercer, and J. S. Mattick (2008)
Science 319, 1787-1789
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)