Integrative profiling of condensation-prone RNAs during early development

Tajda Klobučar; Jona Novljan; Ira A Iosub; Boštjan Kokot; Iztok Urbančič; D Marc Jones; Anob M Chakrabarti; Nicholas M Luscombe; Jernej Ule; Miha Modic

doi:10.1016/j.xgen.2025.101065

Integrative profiling of condensation-prone RNAs during early development

Cell Genom. 2026 Feb 11;6(2):101065. doi: 10.1016/j.xgen.2025.101065. Epub 2025 Nov 19.

Authors

Affiliations

¹ National Institute of Chemistry, Ljubljana, Slovenia; The Francis Crick Institute, London, UK; PhD Program "Biosciences", Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia.
² National Institute of Chemistry, Ljubljana, Slovenia; Department of Genomics and Developmental Biology, Zoological Institute, Karlsruhe Institute of Technology, Karlsruhe, Germany; Institute of Biological and Chemical Systems, Karlsruhe Institute of Technology, Karlsruhe, Germany; Center for Synthetic Genomics (SynGen) Heidelberg-Karlsruhe-Mainz, Germany.
³ The Francis Crick Institute, London, UK; Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Dementia Research Institute at KCL, London, UK.
⁴ J. Stefan Institute, Ljubljana, Slovenia.
⁵ The Francis Crick Institute, London, UK; University College London, UCL Respiratory, London, UK.
⁶ The Francis Crick Institute, London, UK; Okinawa Institute of Science and Technology, Okinawa, Japan.
⁷ National Institute of Chemistry, Ljubljana, Slovenia; The Francis Crick Institute, London, UK; Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Dementia Research Institute at KCL, London, UK.
⁸ National Institute of Chemistry, Ljubljana, Slovenia; The Francis Crick Institute, London, UK; Department of Genomics and Developmental Biology, Zoological Institute, Karlsruhe Institute of Technology, Karlsruhe, Germany; Institute of Biological and Chemical Systems, Karlsruhe Institute of Technology, Karlsruhe, Germany; Center for Synthetic Genomics (SynGen) Heidelberg-Karlsruhe-Mainz, Germany; Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. Electronic address: miha.modic@kit.edu.

Abstract

Complex RNA-protein networks play a pivotal role in the formation of many types of biomolecular condensates. How RNA features contribute to condensate formation, however, remains incompletely understood. Here, we integrate tailored transcriptomics assays to identify a distinct class of developmental condensation-prone RNAs termed "smOOPs" (semi-extractable, orthogonal-organic-phase-separation-enriched RNAs). These transcripts localize to larger intracellular foci, form denser RNA subnetworks than expected, and are heavily bound by RNA-binding proteins (RBPs). Using an explainable deep learning framework, we reveal that smOOPs harbor characteristic sequence composition, with lower sequence complexity, increased intramolecular folding, and specific RBP-binding patterns. Intriguingly, these RNAs encode proteins bearing extensive intrinsically disordered regions and are highly predicted to be involved in biomolecular condensates, indicating an interplay between RNA- and protein-based features in phase separation. This work advances our understanding of condensation-prone RNAs and provides a versatile resource to further investigate RNA-driven condensation principles.

Keywords: OOPS; RIC-seq; RNA-RNA interactions; RNA-protein networks; condensation; condensation-prone RNAs; deep learning; phase separation; semi-extractability.

MeSH terms

Animals
Biomolecular Condensates* / metabolism
Gene Expression Profiling / methods
Humans
Protein Binding
RNA* / chemistry
RNA* / genetics
RNA* / metabolism
RNA-Binding Proteins* / genetics
RNA-Binding Proteins* / metabolism
Transcriptome

Substances

RNA-Binding Proteins
RNA