Ribosomal RNA 2′-O-methylation dynamics impact cell fate decisions
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Dokumenter
- Fulltext
Indsendt manuskript, 5,18 MB, PDF-dokument
Translational regulation impacts both pluripotency maintenance and cell differentiation. To what degree the ribosome exerts control over this process remains unanswered. Accumulating evidence has demonstrated heterogeneity in ribosome composition in various organisms. 2′-O-methylation (2′-O-me) of rRNA represents an important source of heterogeneity, where site-specific alteration of methylation levels can modulate translation. Here, we examine changes in rRNA 2′-O-me during mouse brain development and tri-lineage differentiation of human embryonic stem cells (hESCs). We find distinct alterations between brain regions, as well as clear dynamics during cortex development and germ layer differentiation. We identify a methylation site impacting neuronal differentiation. Modulation of its methylation levels affects ribosome association of the fragile X mental retardation protein (FMRP) and is accompanied by an altered translation of WNT pathway-related mRNAs. Together, these data identify ribosome heterogeneity through rRNA 2′-O-me during early development and differentiation and suggest a direct role for ribosomes in regulating translation during cell fate acquisition.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Developmental Cell |
| Vol/bind | 58 |
| Udgave nummer | 17 |
| Sider (fra-til) | 1593-1609.e9 |
| ISSN | 1534-5807 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
The Lund lab is supported by grants from the Danish Council for Independent Research (Sapere Aude program 418 3-00179B and [0169-00073B]); the Novo Nordisk Foundation (NNF21CC0073729 and NNF 0071919); the Lundbeck Foundation (R198-2015-174); and the Danish Cancer Society (R204-A12532). Furthermore, this project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement n° 801481 and The VILLUM Experiment Programme under the grant n° 17544. The authors would like to thank Bettina Mentz, Anna Fossum, and Elin Josefina Pietras for their technical help. Mass spectrometry analyses were performed by the Proteomics Research Infrastructure (PRI) at the University of Copenhagen (UCPH), supported by the Novo Nordisk Foundation (NNF) (grant agreement number NNF19SA0059305). S.J.H. designed most experiments, collected data, and drafted the article. M.D.J. carried out ribosome profiling, data analysis, interpretation, and mass spectrometry data analysis. K.A. performed bioinformatics data analysis. M.L.K. provided mouse brain samples and insight into brain development and ribosome structure. K.L.A. carried out mass spectrometry data collection. Z.A.-N and A.K. assisted with qPCR data collection and data interpretation. M.F. and D.M.S. were involved in establishing cell lines. P.M. designed and made the CRISPR-Cas9-related constructs. D.M.G. F.S.A. and D.T. provided critical input on the manuscript. N.K. contributed ribosome biogenesis-related experiments. H.N. and A.K. provided advice on data interpretation. A.H.L. and M.D.J. assisted with work conception, data interpretation, and drafting of the manuscript. All authors commented on the manuscript. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.
Funding Information:
The Lund lab is supported by grants from the Danish Council for Independent Research (Sapere Aude program 418 3-00179B and [0169-00073B] ); the Novo Nordisk Foundation (NNF21CC0073729 and NNF 0071919 ); the Lundbeck Foundation ( R198-2015-174 ); and the Danish Cancer Society ( R204-A12532 ). Furthermore, this project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement n° 801481 and The VILLUM Experiment Programme under the grant n° 17544 . The authors would like to thank Bettina Mentz, Anna Fossum, and Elin Josefina Pietras for their technical help. Mass spectrometry analyses were performed by the Proteomics Research Infrastructure (PRI) at the University of Copenhagen (UCPH), supported by the Novo Nordisk Foundation (NNF) (grant agreement number NNF19SA0059305 ).
Publisher Copyright:
© 2023 Elsevier Inc.
Antal downloads er baseret på statistik fra Google Scholar og www.ku.dk
ID: 367600954