LIN28 plays a critical role in developmental transition, glucose metabolism, and tumorigenesis. At the molecular level, LIN28 is known to repress maturation of let-7 microRNAs and enhance translation of certain mRNAs. In this study, we obtain a genome-wide view of the molecular function of LIN28A in mouse embryonic stem cells by carrying out RNA crosslinking-immunoprecipitation- sequencing (CLIP-seq) and ribosome footprinting. We find that, in addition to let-7 precursors, LIN28A binds to a large number of spliced mRNAs. LIN28A recognizes AAGNNG, AAGNG, and less frequently UGUG, which are located in the terminal loop of a small hairpin. LIN28A is localized to the periendoplasmic reticulum (ER) area and inhibits translation of mRNAs that are destined for the ER, reducing the synthesis of transmembrane proteins, ER or Golgi lumen proteins, and secretory proteins. Our study suggests a selective regulatory mechanism for ER-associated translation and reveals an unexpected role of LIN28A as a global suppressor of genes in the secretory pathway.
Bibliographical noteFunding Information:
We are grateful to Huili Guo for advice on ribosome profiling and Daehyun Baek for critical comments on the manuscript. We also thank Ahyoung Cho and Yun Cheng Chang for technical help and members of our laboratory for discussion. This work was supported by the Research Center Program (EM1202) of IBS (Institute for Basic Science); the BK21 Research Fellowships (J.C., H.C., S.C.K., and B.K.) from the Ministry of Education, Science and Technology of Korea; the TJ Park Postdoctoral Fellowship (Y.K.); and the National Honor Scientist Program (20100020415) through the National Research Foundation of Korea (NRF).
ASJC Scopus subject areas
- General Biochemistry,Genetics and Molecular Biology