Summary of the findings, from the authors:
RNA, specifically mRNA, has been the focus during the pandemic, saving millions of lives as the main component of the COVID-19 vaccine. The presence of a critical RNA modification in the mRNA was key to the successful development of vaccines.
RNA modification acts as a marker that directs the fate of the RNA. Numerous RNA modifications have been reported in recent years, with N6-Methyladenosine (m6A) being the most abundant modification in mRNA. The m6A modification plays a crucial role in regulating post-transcriptional RNA processes, including splicing, export, stability, turnover, translation, and it has key roles in cell differentiation and reprogramming, gametogenesis, embryogenesis, stress response, and tumorigenesis.
Identifying the distribution of m6A in cells is essential for understanding this important marker in embryogenesis and pathogenesis. However, conventional m6A detection strategies require large amounts of RNA as starting material, hindering application to scarcely available cell types and tissues, such as early embryos and cancer biopsies. This highlights the need to develop an m6A profiling method capable of identifying m6A sites from low cell numbers and even single cells.
In a recent Nature Biotechnology paper, researchers from Oslo University Hospital, together with collaborators listed below, have developed picogram-scale m6A RNA immunoprecipitation and sequencing (picoMeRIP-seq) to study m6A in vivo in single cells and scarce cell types. This technology will enable m6A profiling of scarce cell types from in vivo sources, such as embryos and biopsies from healthy and diseased tissues.
Characterizing the m6A landscape in mouse preimplantation embryos
The m6A marking and dynamics on RNA in oocytes and early embryos have for a long time remained unknown due to the low number in which these can be obtained. In another study published in Nature Structural and Molecular Biology, the picoMeRIP-seq technology was applied to produce detailed maps of m6A in mouse oocytes and preimplantation embryos. This work discovered novel patterns of the m6A modification on transcribed genes (mRNA) inherited from the mother compared to mRNA from genes activated in the embryo’s genome after fertilization in regard to targeting and regulation. These results lay the foundation for future studies exploring the regulatory roles of m6A in mammalian early embryo development.
Opens the door for broad applications in disease-related scarce samples
This breakthrough technology not only provides a valuable tool and new insight into early embryogenesis, but also opens the door for m6A mapping from small pieces of human tissue, such as cancer biopsies and healthy tissue. It therefore holds promise to allow researchers to understand the role of m6A in development and progression of diseases. Future studies using this technology may help to identify pathways and mechanisms involved in diseases and provide novel candidates for therapeutic targeting.
The project is a multi-institutional project with contributions from:
- Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- University of Michigan, Ann Arbor, MI, USA
- The Ohio State University, Columbus, OH, USA
- Department of Reproductive Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Norwegian Transgenic Centre, University of Oslo, Oslo, Norway
- Norwegian University of Life Sciences, Aas, Norway
- University of Copenhagen, Copenhagen, Denmark
- Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, USA
- KU Leuven-University of Leuven, Leuven, Belgium
- Department of Molecular Medicine, University of Oslo, Oslo, Norway
- School of Life Sciences, Inner Mongolia University, Hohhot, China
Single-cell m6A mapping in vivo using picoMeRIP-seq.
Li Y, Wang Y, Vera-Rodriguez M, Lindeman LC, Skuggen LE, Rasmussen EMK, Jermstad I, Khan S, Fosslie M, Skuland T, Indahl M, Khodeer S, Klemsdal EK, Jin KX, Dalen KT, Fedorcsak P, Greggains GD, Lerdrup M, Klungland A, Au KF, Dahl JA.
Nat Biotechnol. 2023 Jun 22. doi: 10.1038/s41587-023-01831-7. Online ahead of print.
The RNA m6A landscape of mouse oocytes and preimplantation embryos.
Wang Y, Li Y, Skuland T, Zhou C, Li A, Hashim A, Jermstad I, Khan S, Dalen KT, Greggains GD, Klungland A, Dahl JA, Au KF.
Nat Struct Mol Biol. 2023 May;30(5):703-709. doi: 10.1038/s41594-023-00969-x. Epub 2023 Apr 20.
Yanjiao Li, first author