TUT4 in Concert with Lin28 Suppresses MicroRNA Biogenesis through Pre-MicroRNA Uridylation

Heo, I., Joo, C., Kim, Y.-K., Ha, M., Yoon, M.-J., Cho, J., Yeom, K.-H., Han, J.,and Kim, V. N.

Cell 138, 696–708, 2009

Speaker：Yu-Chan, Yang (楊于嬋)                                      Time：14:00~15:00, Jan. 06 2010

Commentator：Dr. Cheng-Chan Lu (呂政展 教授)           Place：Room 601

Abstract：

MicroRNAs (miRNAs) are the key regulators in cellular functions. miRNAs are generated via two-step processing, including cropping a primary transcript of miRNA gene (pri-miRNA) into a hairpin-structured precursor (pre-miRNA) and exporting a  pre-miRNA to cytoplasm and further processing it into a mature miRNA. Lin28, a pluripotency factor, can inhibit the biogenesis of miRNA let-7. Lin28 functions by binding to precursor let-7(pre-let-7) in cytoplasm to induce uridylation of pre-let-7(1,2). The authors identified a noncanonical poly (A) polymerase, TUT4ase (TUT4) which is the uridylyl transferase for pre-let-7. Lin28 recognizes a conserved sequence motif, GGAG, of pre-let-7 in the terminal loop and recruits TUT4 to proceed uridylation. TUT4 then adds a uridine tail to the 3’ end of pre-miRNA which inhibits miRNA biogenesis. Other three pre-miRNAs (pre-miR-107, 143, 200c), which are more abundantly observed in differentiated cells than in undifferentiated cells are modestly regulated by Lin28 and TUT4(2). Knockdown of Lin28 and TUT4 decreases the pluripotency markers Oct4 and Nanog which are transcription factors required to maintain the pluripotency and self-renewal of embryonic stem cells. (3) It indicates that both of them are required for stem cells (ES) to maintain pluripotency. In summary, ES development is through Lin28 recruitment of TUT4 to uridylate the pre-miRNA and to suppress the miRNA biogenesis. In addition, the uridylation assay may provide a way to screen for chemicals that affect let-7 biogenesis, which may be useful for stem cell engineering and cancer therapy.

References：

1.      Heo, I., Joo, C., Cho, J., Ha, M., Han, J., and Kim, V.N. (2008). Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol. Cell 32, 276–284.

2.      Bussing, I., Slack, F.J., and Grosshans, H. (2008). let-7 microRNAs in development, stem cells and cancer. Trends Mol. Med. 14, 400–409.

3. Loh Y.-H. et. al (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nature Genetics. 38, 431-440.