Identification of FBLL1 as a neuron- specific RNA 2′- O- methyltransferase mediating neuronal differentiation

• 成果类型: Article
• 署名作者: Zhang, Deyu; Li, Bo; Xu, Henan; Li, Jingying; Ma, Chao; Ge, Wei; Lu, Congcong; Cao, Xuetao
• 署名单位: Nankai University; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Chinese Academy of Medical Sciences - Peking Union Medical College
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10859
• DOI: 10.1073/pnas.2406961121
• 发表日期: 2024-11-26
• 关键词: gene-expression; 2'-o-methylation; methylation

摘要

2 '- O- methylation is one of the most prevalent RNA modifications found in different RNA types. However, the identities of enzymes participating in the transfer of methyl groups are not well defined. To date, fibrillarin (FBL) is the only known small nucleolar ribonucleoprotein (snoRNP) 2 '- O- methyltransferase. Whether other snoRNP 2 '- O- methyltransferases exist and their functions in targeting RNAs to determine cell differentiation and function need to be elucidated. Here, we identify FBL-like protein 1 (FBLL1) as a 2 '- O- methyltransferase and find its function in promoting neuronal differentiation. We show that FBLL1 is a key snoRNP complex enzyme that transfers methyl groups to substrate RNAs both in vitro and in vivo. Moreover, FBLL1 exhibits different 2 '- O- methyltransferase site selectivity from FBL and tissue- specific distribution. FBLL1 is preferentially expressed in the brain, especially in human neuron cells, and promotes neuronal differentiation through 2 '- O- methylation of GAP43 messenger RNA (mRNA). Knockdown of FBLL1, but not FBL, reduced 2 '- O- methylation levels in GAP43 mRNA, decreased expression of GAP43 proteins, and eventually repressed neuronal differentiation. Our finding of neuron- specific FBLL1 adds insights into RNA modification in neurobiology and provides clues for understanding 2 '- O- methylation in health and disease.