Sphingomyelin regulates the transcriptional machinery in nuclear lipid microdomains
Nuclear lipid microdomains rich in sphingomyelin and cholesterol content regulate double-stranded exonuclease-resistant RNA. The study aimed to elucidate the importance of nuclear lipid microdomains in safeguarding nuclear RNA from digestion and to scrutinize all RNA present. Thus, we investigated the impact of sphingomyelinase on nuclear lipid microdomain RNA and conducted RNA extraction, library preparation, and sequencing. Sphingomyelinase treatment makes the RNA susceptible to RNase treatment. Nuclear lipid microdomains exhibit a higher abundance of retained introns, small nuclear RNA, and long intergenic non-coding RNA compared to whole nuclei, with a notable enrichment in miRNA. The high concentration (20%) of miRNAs in nuclear lipid microdomains is justified by the presence of specific nuclear circular RNA as exons circularized with 'retained' introns, referred to as exon-intron circular RNA (EIciRNA) that act as a sponge for miRNAs. Moreover, we demonstrate the presence of ciRNA. The functional analysis indicates that all types of RNase-resistant RNA associated with nuclear lipid microdomains are involved in chromatin organization and brain pathophysiology. In conclusion, nuclear lipid microdomains represent a site of transcription regulation in which circular RNAs, miRNA, and double-stranded mRNA, all resistant to RNase, are stabilized by nuclear sphingomyelin.
Authors
- Ornella Calderini (ORCID: https://orcid.org/0000-0001-9516-8997)
- Paola Signorelli (ORCID: https://orcid.org/0000-0003-2368-2393)
- Carmela Conte (ORCID: https://orcid.org/0000-0003-2456-6300)
- Federico Fiorani (ORCID: https://orcid.org/0009-0007-7983-1294)
- Michele Dei (ORCID: https://orcid.org/0000-0001-7359-8558)
- Nario Tomishige (ORCID: https://orcid.org/0000-0002-1266-5400)
- Francesco Curcio (ORCID: https://orcid.org/0000-0002-9070-4807)
- Cataldo Arcuri (ORCID: https://orcid.org/0000-0002-3114-8812)
- Samuela Cataldi
- Nicolò Gualandi (ORCID: https://orcid.org/0000-0003-0622-6118)
- Elisabetta Albi (ORCID: https://orcid.org/0000-0002-5745-5343)
- Toshihide Kobayashi (ORCID: https://orcid.org/0000-0002-4811-7270)
- Alessandra Mirarchi (ORCID: https://orcid.org/0009-0004-2538-8686)
- Rita Clara Paroni (ORCID: https://orcid.org/0000-0002-3186-8860)
- Michela Bulfoni (ORCID: https://orcid.org/0000-0003-2646-4228)
- Mercedes Garcia‐Gil (ORCID: https://orcid.org/0000-0002-1344-2786)
- Tommaso Beccari (ORCID: https://orcid.org/0000-0001-9637-6579)
- Giorgia Vesca
Institutions
- University of Pisa (IT)
- University of Udine (IT)
- Centre National de la Recherche Scientifique (FR)
- University of Milan (IT)
- University of Perugia (IT)
- IRCCS Policlinico San Donato (IT)
- Institute of Biosciences and Bioresources (IT)
- RIKEN (JP)
- Université de Strasbourg (FR)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1038/s42003-025-08697-2
- Primary Topic
- Circular RNAs in diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Università degli Studi di Milano