Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Dec;22(1):1-22.
doi: 10.1080/15476286.2025.2563986. Epub 2025 Oct 3.

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

Michelle Ninochka D'Souza  1   2 , Naveen Kumar Chandappa Gowda  1   2   3 , Nivedita Hariharan  2 , Syed Wasifa Qadri  1   4 , Dasaradhi Palakodeti  2 , Ravi S Muddashetty  1
Affiliations

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

Michelle Ninochka D'Souza et al. RNA Biol. 2025 Dec.

Abstract

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.

Keywords: FMRP; Ribosomal RNA; epitranscriptome; ribosome; snoRNA.

PubMed Disclaimer

Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Changes in 2’O-Methylation pattern of rRNA along neuronal differentiation of H9 ESCs.
Figure 2.
Figure 2.
Altered 2’O-Methylation pattern along neuronal differentiation in the absence of FMRP.
Figure 3.
Figure 3.
The interaction of FMRP with C/D box snoRNA determines the extent of methylation.
Figure 4.
Figure 4.
Altered 2’O-methylation affects translation in ESCs and NSCs.
Figure 5.
Figure 5.
Altering 2’O-Methylations on ribosomes during neuronal differentiation.
See this image and copyright information in PMC

References

    1. Tahmasebi S, Amiri M, Sonenberg N.. Translational control in stem cells. Front Genet. 2019;9:709. doi: 10.3389/fgene.2018.00709 - DOI - PMC - PubMed
    1. Gabut M, Bourdelais F, Durand S. Ribosome and translational control in stem cells. Cells. 2020;9(2):497. doi: 10.3390/cells9020497 - DOI - PMC - PubMed
    1. Young RA. Control of the embryonic stem cell state. Cell. 2011;144(6):940–954. doi: 10.1016/j.cell.2011.01.032 - DOI - PMC - PubMed
    1. Häfner SJ, Jansson MD, Altinel K, et al. Ribosomal RNA 2′-O-methylation dynamics impact cell fate decisions. Dev Cell. 2023;58(17):1593–1609.e9. doi: 10.1016/j.devcel.2023.06.007 - DOI - PubMed
    1. Henras AK, Plisson-Chastang C, O’Donohue M-F, et al. An overview of pre-ribosomal RNA processing in eukaryotes: pre-ribosomal RNA processing in eukaryotes. Wiley Interdiscip Rev RNA. 2015;6(2):225–242. doi: 10.1002/wrna.1269 - DOI - PMC - PubMed

MeSH terms

Substances

LinkOut - more resources