Mechanistic study of regulation of let-7 miRNA biogenesis by LIN28A in the nucleus

Abstract

LIN28A has emerged as a key regulator of various biological pathways in embryonic stem cells (ESCs), however the regulatory mechanism by which LIN28A-mediated miRNA processing in the nucleus contributes to pluripotency is largely unknown. Here, we show that SET7/9, a histone mono-methyltransferase, associates with LIN28A. SET7/9-mediated methylation increases LIN28A nuclear reten-tion and protein stability as well as multimerization of nuclear LIN28A to pri-let-7 miRNA. Using an RNAi knockdown approach, we reveal that nuclear LIN28A functions in the nucleoli of ESCs by sequestering the pri-let-7 and blocking its processing via a TUTase-independent mechanism. The nuclear LIN28A regulates transcriptional changes of MYC-pathway targets through maximum inhibition of let-7 biogenesis, thereby maintaining stemness and inhibiting differentiation by modulating stem cell and early lineage-specific mark-ers. These findings provide new insight into the molecular mechanism underlying the post-translational meth-ylation of nuclear LIN28A and its ability to modulate pluripotency by controlling pri-let-7 miRNAs in human ESCs.