Work

Probing the complexity of cellular RNA folding: Ensembles, intermediates, and isoforms

Year: 2026

Type: review

Abstract: RNA molecules populate complex structural landscapes that are continuously reshaped throughout the RNA lifecycle by equilibrium and non-equilibrium processes. Resolving these structural landscapes represents a central challenge in RNA biochemistry. We review recent advances in RNA chemical probing, sequencing, and computational deconvolution technologies that are revolutionizing our ability to measure the complexities of RNA folding in cells and the deep involvement of these complexities in RNA functional mechanisms. We highlight new methods for deconvolving structural ensembles, distinguishing isoform-specific architectures using long-read sequencing, capturing co-transcriptional folding intermediates in vivo, and measuring higher-order RNA structures while also underscoring remaining challenges. We conclude by outlining future directions in probe development, sequencing, and integrative modeling, and discuss how resolving RNA structural ensembles with increasingly high resolution will likely reveal new therapeutic opportunities to selectively target functional RNA heterogeneity.

Source: Current Opinion in Structural Biology

DOI: 10.1016/j.sbi.2026.103347

Authors: Anthony M. Mustoe, Danny Incarnato

Institutions: Baylor College of Medicine, University of Groningen

Language: English

Topic: RNA and protein synthesis mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: hybrid

Estimated APC paid: $4,360

Funders: Arnold and Mabel Beckman Foundation, G. Harold and Leila Y. Mathers Foundation, National Institutes of Health, European Research Council