Altering rRNA 2’O-methylation pattern during neuronal differentiation is regulated by FMRP

• 出版年: RNA Biology
• 主要な著者: Michelle Ninochka D’Souza, Naveen Kumar Chandappa Gowda, Nivedita Hariharan, Syed Wasifa Qadri, Dasaradhi Palakodeti, Ravi S Muddashetty
• フォーマット: 論文
• 言語: 英語
• 出版事項: Taylor & Francis Group 2025-12-01
• 主題: FMRP; ribosome; snoRNA; epitranscriptome; Ribosomal RNA
• オンライン･アクセス: https://www.tandfonline.com/doi/10.1080/15476286.2025.2563986
• ISSN: 1547-6286; 1555-8584

The Fragile X Messenger Ribonucleoprotein (FMRP) is a selective RNA-binding protein that localizes to the cytoplasm and the nucleus. The loss of FMRP results in Fragile X Syndrome (FXS), an autism spectrum disorder. FMRP interacts with ribosomes and regulates the translation of mRNAs essential for neuronal development and synaptic plasticity. However, the biochemical nature of this translation regulation is unknown. Here, we report that a potential feature of FMRP-mediated translation regulation during neuronal differentiation is the modulation of 2’-O-methylation of ribosomal RNA. 2’O-methylation, facilitated by C/D box snoRNAs in the nucleus, is a major epitranscriptome mark on rRNA, essential for ribosome assembly and function. We found that FMRP influences a distinct rRNA 2’O-Methylation pattern across neuronal differentiation. We show that in H9 ESCs, FMRP interacts with a selected set of C/D box snoRNA in the nucleus, resulting in the generation of ribosomes with a distinct pattern of rRNA 2’O-Methylation. This epitranscriptome pattern on rRNA undergoes a significant change during the differentiation of ESCs to neuronal precursors and cortical neurons. ESCs exhibit substantial levels of hypomethylated residues on rRNA, which progressively decrease in neuronal precursors and post-mitotic cortical neurons. This reduction correlates with changes in global protein synthesis across different stages of differentiation. Importantly, this stepwise change in the 2’O-methylation pattern during neuronal differentiation is altered in the absence of FMRP, which could impact neuronal development and contribute to dysregulated protein synthesis observed in Fragile X Syndrome.