Charting a Future for Sequencing RNA and Its Modifications A New Era for Biology and Medicine (2024) / Chapter Skim
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Through exquisite natural biological pathways, RNA is edited and revised to give rise to hundreds, in some cases thousands, of distinct RNA molecules for each gene. In this way, RNA molecules allow diversification of the information encoded by DNA, which is essential for the maintenance and survival of complex organisms, including humans.
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Existing technologies cannot currently discover all RNA modifications, let alone comprehensively sequence them on every RNA molecule. This limitation significantly hampers the ability to study and leverage RNA modifications to address current and emerging societal issues.
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FIGURE S-1 Key efforts needed to unlock any epitranscriptome. NOTE: Expanding research; advancing experimental and computational tools and technology; developing references and standards of various types; establishing stable, integrated, and centralized data resources; and cultivating innovation across several dimensions, including workforce development, are necessary to fully reveal any epitranscriptome.
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Like the United States, several countries are funding research in this area, with a few leading focused initiatives. Germany has dedicated significant public funding to RNA modifications, and Australia and Canada are also making major investments in this space, with efforts focused on RNA chemistry and RNA-based therapeutics.
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Thus there is a critical need in the field to improve the sensitivity, specificity, and throughput of technologies that currently exist, and to explore new and emerging instrumentation and methodologies for enhancing capabilities for sequencing RNA modifications and determining their abundance and stoichiometry. A key milestone on the way to this goal is establishing the ability to sequence RNA molecules from end to end, to preserve information about all their modifications.
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A broader collection of modified RNAs with known sequence and modification stoichiometry is needed to compare results collected using different methods, within and between labs. Although synthetic routes for generating modified nucleosides exist in many cases, few commercial or nonprofit sources are available for these standards.
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FIGURE S-2 Roadmap for advancing tools and technologies. NOTES: Colored points represent actions needed for progress; check marks indicate milestones along the path for achieving the 15-year vision of mapping epitranscriptomes.
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NOTES: Colored points represent actions needed for progress; check marks indicate milestones for creating reference standards and data and database standards to reach the goal of having readily available, affordable modified oligonucleotide reference standards and seamless access to information on modified RNAs from any defined set of cellular conditions within 15 years. 8 Prepublication Copy
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This poses the risk of limiting scientific growth and understanding, while wasting time, effort, and resources. Centralized administration of RNA data resources is needed to ensure sustainable funding and stability, so that the current knowledge on RNA modifications can be integrated and new modifications can be indexed.
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Several opportunities and training programs that already exist through NSF, the National Institute of General Medical Sciences, and the Howard Hughes Medical Institute can be adapted or expanded, in consultation with education and pedagogy experts and scientific societies with expertise in RNA, to emphasize RNAfocused research and career paths. Individuals already in the workforce can make important contributions to advancing the study of RNA science and the application of epitranscriptomics, if they are offered professional development, retraining, and continuing education opportunities tailored to their needs.
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workforce with interdisciplinary expertise. POTENTIAL OUTCOMES AND BROADER IMPACTS In addition to the novel RNA sequencing tools, technologies, computational methods; data infrastructure; and workforce benefits that would come from a large-scale initiative focused on epitranscriptomics, numerous other practical payoffs and broader impacts on society would result from such an initiative.
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In its essence, the goal of all biomedical science is to relieve human suffering and maintain human health. Time, effort, and money invested in this epitranscriptome initiative relates to this goal directly and will provide information helpful to numerous enterprises, including those listed above.
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