期刊
CELL STEM CELL
卷 15, 期 6, 页码 735-749出版社
CELL PRESS
DOI: 10.1016/j.stem.2014.10.016
关键词
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资金
- Stem Cell Research Program [2011-0019509, 2012M 3A9B 4027953]
- Basic Science Research Program [NRF-2012R1A6A3A01038981]
- KAIST Future Systems Healthcare Project
- Intelligent Synthetic Biology Center of Global Frontier Project - Ministry of Science, ICT and Future Planning [2011-0031955]
- Welch Foundation [I-1786]
- Klingenstein Fund
- National Institute of Neurological Disorders and Stroke [R01NS085418]
LIN28-mediated processing of the microRNA (miRNA) let-7 has emerged as a multilevel program that controls self-renewal in embryonic stem cells. LIN28A is believed to act primarily in the cytoplasm together with TUT4/7 to prevent final maturation of let-7 by Dicer, whereas LIN28B has been suggested to preferentially act on nuclear processing of let-7. Here, we find that SET7/9 monomethylation in a putative nucleolar localization region of LIN28A increases its nuclear retention and protein stability. In the nucleoli of human embryonic stem cells, methylated LIN28A sequesters pri-let-7 and blocks its processing independently of TUT4/7. The nuclear form of LIN28A regulates transcriptional changes in MYC-pathway targets, thereby maintaining stemness programs and inhibiting expression of early lineage-specific markers. These findings provide insight into the molecular mechanism underlying the post-translational methylation of nuclear LIN28A and its ability to modulate pluripotency by repressing let-7 miRNA expression in human embryonic stem cells.
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