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The regulatory logic of 170+ RNA modifications is largely unknown
Problem statement
Over 170 post-transcriptional RNA modifications are currently known, but how these modifications interact with one another and create multi-layered, dynamic regulatory networks within cells — and how they govern organismal phenotype — is, in the words of the NSF PPM letter, "the challenge now." The letter describes the central dogma as having expanded beyond a flow of information from DNA to RNA to protein into a system of complex interactions and feedback loops among these macromolecules and their many isoforms and chemically modified variants. Among the questions it calls largely unexplored: how multiple modifications influence each other on the same or different RNAs, and why the same modification can have different effects on different classes of RNA. The letter says that characterizing multiple modifications on individual RNAs or proteins in a quantitative way "is only just beginning," and the MFB solicitation calls for proposals that develop tools, methodology, and/or theory to study RNA structure, interactions, and functions at molecular or genome- and transcriptome-wide scales, with relevance to physiological conditions.
Why this matters
RNA modifications are found in all major RNA classes (tRNA, mRNA, and rRNA) across all three domains of life, and the PPM letter notes that numerous developmental and physiological disorders have been linked to defects in modification pathways. The MFB solicitation prioritizes RNA research with potential for biotechnology applications in economic sectors such as agriculture or energy production, or that help mitigate the effects of climate change, improve environmental sustainability, or combat global pandemics.
What’s been tried and why it hasn’t worked
Strategies developed to characterize single RNA and protein modifications can be applied to populations of molecules, but the NSF PPM DCL says the quantitative characterization of multiple modifications on individual RNAs or proteins is only just beginning. The letter gives lower priority to projects focused on relatively well-studied single modifications (its example is a specific modification on a histone tail) and higher priority to proposals that tackle complexity on a systems scale. The MFB solicitation prioritizes research on how RNA processing, epitranscriptomic modification, or organization in macromolecular complexes or compartments such as condensates relates to cellular activities. It also seeks to catalyze synergies among researchers in the biological, chemical, computational, mathematical, and physical sciences, and requires every proposal to take an interdisciplinary approach.
What would unlock progress
Novel tools and methodologies for studying RNA structure, interactions, and functions at molecular or genome/transcriptome-wide scales, with relevance to physiological conditions. Understanding how complex combinations of post-transcriptional and post-translational modifications interact to form dynamic regulatory networks. Generalizable approaches that extend beyond specific model systems. Computational methods that enable prediction and analysis of the structure and function of RNA and its modified forms. Translation of fundamental discoveries into biotechnology applications.
Entry points for student teams
A student team could use publicly available RNA modification databases (RMBase, MODOMICS) and transcriptome-wide modification mapping datasets to computationally identify patterns of co-occurring RNA modifications across different cell types or organisms, testing whether specific modification combinations correlate with transcript stability or translation efficiency. Alternatively, a team with wet-lab access could develop a simplified method for profiling one RNA modification type across the transcriptome using commercially available antibodies and sequencing. Relevant skills: RNA biology, bioinformatics, computational biology, chemistry, data science.
Genes
Structural cousins: stuck the same way, in other fields
Sources
"Molecular Foundations for Biotechnology (MFB): Partnerships to Transform Emerging Industries – RNA Tools/Biotechnology," Program Solicitation NSF 24-607, (accessed 2026-02-15); "Dear Colleague Letter: Posttranscriptional and Posttranslational Modification (PPM)," NSF 24-084, (accessed 2026-10-01). go to source 1 ↗ go to source 2 ↗
Working notes
Notes made while writing and checking this brief, shown as written. They use working shorthand.
- The MFB program specifically funds RNA tools and biotechnology development; proposals must aim to develop and test tools, methodology, and/or theory.
- The PPM DCL gives lower priority to projects focused on relatively well-studied single modifications and higher priority to proposals that tackle complexity on a systems scale.
- Cross-domain connection: shares structure with `bio-genotype-phenotype-prediction-gap` (RNA modification is one of the layers connecting genotype to phenotype) and `bio-cell-measurement-tool-gap` (both identify measurement capability as the primary bottleneck).
- The `temporal:newly-tractable` tag applies because, per the PPM DCL, the quantitative characterization of multiple modifications on individual RNAs or proteins "is only just beginning."
- The `failure:disciplinary-silo` tag is central — the MFB solicitation seeks synergies among researchers in the biological, chemical, computational, mathematical, and physical sciences.
Reconciliation 2026-10-01: Fact repair after reading the whole write-up against both sources it names. Both were fetched on 2026-10-01 directly from nsf.gov and read in full: the MFB solicitation NSF 24-607 (https://www.nsf.gov/funding/opportunities/mfb-molecular-foundations-biotechnology/506142/nsf24-607/solicitation, posted September 13, 2024, now marked archived) and the PPM Dear Colleague Letter NSF 24-084 (https://www.nsf.gov/funding/opportunities/dcl-posttranscriptional-posttranslational-modification-ppm/nsf24-084, dated May 2, 2024, now marked archived). Both are short funding calls and support less than the write-up said. (1) The Source line gave the first title as "MFB: Molecular Foundations for Biotechnology — RNA Tools/Biotechnology"; the solicitation's own title is "Molecular Foundations for Biotechnology (MFB): Partnerships to Transform Emerging Industries – RNA Tools/Biotechnology," and the line now carries it. The letter had no link; its address was added. (2) The sentence that a key unsolved question is how "reader" and "eraser" proteins tell one modification from another was removed; neither source mentions readers or erasers. It now gives two questions the letter calls largely unexplored. (3) "Remains deeply unresolved," RNA as "not the passive intermediate," and tools being "insufficient" were stronger than the sources; the paragraph now uses the letter's wording ("the challenge now," "is only just beginning") and says what the solicitation calls for. (4) Removed because neither source contains them: RNA therapeutics as a market of more than $50 billion; mRNA vaccines, antisense oligonucleotides and siRNA drugs; development by trial and error; crop trait engineering, biofuel pathways and carbon fixation as examples; and the comparison of the epitranscriptome with epigenetics. The section now gives the letter's statements that modifications occur in all major RNA classes across all three domains of life and that disorders have been linked to defects in modification pathways, and the solicitation's list of application areas (agriculture, energy production, climate, environmental sustainability, pandemics). (5) The example "m6A methylation" is not in the sources (the letter's example is a modification on a histone tail), and the letter does not give a reason for its lower priority; the sentence now says what the letter says. (6) Removed or softened because the sources do not say them: that current methods "lack the resolution" to follow RNA activity "in real time"; that biology labs lack chemistry expertise and chemists lack biological context; and that most existing tools were built for specific model systems and do not generalize. The paragraph now reports what the solicitation prioritizes and asks for. (7) In "What Would Unlock Progress," the computational item now follows the solicitation's example (prediction and analysis of the structure and function of RNA and its modified forms), and "under physiological conditions" became "with relevance to physiological conditions"; the sentence on generalizable approaches is left as written, because the solicitation's review criteria ask for outcomes "generalizable beyond the specific system under study." (8) In the notes above, the inference that NSF sees tooling as "a primary bottleneck," the list of nanopore sequencing, cryo-EM and high-throughput biochemistry, and the field-by-field glosses in the silo note are not in the sources and were replaced with what the sources say. Confirmed in the sources and left as written: "over 170" currently known RNA modifications, and the title's "170+" and "largely unknown" (the letter says "largely unexplored"); modifications creating multi-layered, dynamic regulatory networks that govern organismal phenotype; feedback loops among DNA, RNA, protein and their isoforms and modified variants; lower priority for single, well-studied modifications. The MODOMICS database named in the entry points was opened (https://genesilico.pl/modomics/) and is public. RMBase's own site (rna.sysu.edu.cn) refused the connection from here, but its home page was read in an Internet Archive copy from April 2026 (RMBase v3.0, with a Download section), so it is left named as written. Genome tags untouched. A second reader went over these repairs on the same day, confirmed each against the two sources, restored the generalizable-approaches sentence, and changed "tools, methodology, and theory" to the solicitation's "tools, methodology and/or theory."