title: SET7/9 methylation of the pluripotency factor LIN28A is a nucleolar localization mechanism that blocks let-7 biogenesis in human ESCs.
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.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Seung-Kyoon
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Hosuk
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Kyumin
authors.initials: K
authors.lastname: Han
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul 135-710, Republic of Korea.
authors.forename: Sang Cheol
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Yoonjung
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Geunu
authors.initials: G
authors.lastname: Bak
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Younghoon
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Jung Kyoon
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
authors.forename: Tae-Kyung
authors.initials: TK
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea. Electronic address: ymhan@kaist.ac.kr.
authors.forename: Yong-Mahn
authors.initials: YM
authors.lastname: Han
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea. Electronic address: daeyoup@kaist.ac.kr.
authors.forename: Daeyoup
authors.initials: D
authors.lastname: Lee
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D002466:Cell Nucleolus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000502:physiology*; D016259:Genes, myc / Q000502:physiology; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D008745:Methylation; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000502:physiology*; D055503:Protein Multimerization; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C511130:TUT4 protein, human; C487931:mirnlet7 microRNA, human; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human