SET7/9 Methylation of the Pluripotency Factor LIN28A Is a Nucleolar Localization Mechanism that Blocks let-7 Biogenesis in Human ESCs

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. [Display omitted] •LIN28A is modified by methylation at K135 by the monomethyltransferase SET7/9•SET7/9-mediated methylation triggers a switch, causing nuclear retention of LIN28A•This methylation increases the stability and pri-let-7-binding ability of LIN28A•The multimerization of nuclear LIN28A with pri-let-7 maximally blocks its biogenesis Kim et al. reveal that LIN28A is a substrate for methylation by SET7/9 and that methylated LIN28A multimerizes to sequester pri-let-7 in the nucleoli of hESCs. This mechanism prevents nuclear pri-let-7 biogenesis, thereby regulating pluripotency and differentiation of hESCs.