SET7/9 methylation of the pluripotency factor LIN28A is a nucleolar localization mechanism that blocks let-7 biogenesis in human ESCs

Seung Kyoon Kim, Hosuk Lee, Kyumin Han, Sang Cheol Kim, Yoonjung Choi, Sang Wook Park, Geunu Bak, Younghoon Lee, Jung Kyoon Choi, Tae Kyung Kim, Yong Mahn Han, Daeyoup Lee

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

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 posttranslational methylation of nuclear LIN28A and its ability to modulate pluripotency by repressing let-7 miRNA expression in human embryonic stem cells.

Original languageEnglish (US)
Pages (from-to)735-749
Number of pages15
JournalCell Stem Cell
Volume15
Issue number6
DOIs
StatePublished - Dec 4 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Kim, S. K., Lee, H., Han, K., Kim, S. C., Choi, Y., Park, S. W., Bak, G., Lee, Y., Choi, J. K., Kim, T. K., Han, Y. M., & Lee, D. (2014). SET7/9 methylation of the pluripotency factor LIN28A is a nucleolar localization mechanism that blocks let-7 biogenesis in human ESCs. Cell Stem Cell, 15(6), 735-749. https://doi.org/10.1016/j.stem.2014.10.016