Circular RNAs (circRNAs) are loop-shaped molecules that can influence gene regulation through interactions with microRNAs (miRNAs). This matters because circRNAs can exist as different full-length isoforms, and their back-splice junction (BSJ) connects the two ends of the RNA. Treating a circular RNA like a linear transcript can therefore overlook sequence information near this junction.
A research team was led by Professor Giltae Song along with his colleagues from the School of Computer Science and Engineering at Pusan National University, South Korea, who developed circMAC, an AI bioinformatics tool for predicting candidate microRNA binding sites on circular RNAs. The framework takes a full-length circRNA isoform and a mature miRNA as inputs and predicts a binding probability for every circRNA nucleotide. This paper was made available online on 9 September 2026 and was published in Volume 27, Issue 5 of the Briefings in Bioinformatics on 9 September 2026.
"The key advance is moving beyond asking whether a circRNA and miRNA interact to asking where that interaction is likely to occur," said Prof. Song.
To preserve the distinctive circular sequence, circMAC combines three complementary sequence-modeling approaches. Attention captures information from across the circRNA, Mamba models sequential dependencies, and a one-dimensional convolutional neural network identifies short local sequence patterns associated with binding sites. Circular padding in the convolutional branch allows patterns spanning the BSJ to be considered continuously rather than interrupted at the sequence boundary. The model also uses cross-attention to incorporate information from the specific miRNA being analyzed, allowing each circRNA nucleotide to be evaluated in its miRNA-specific context. It also uses structure-aware pretraining based on base-pairing prediction.
The researchers evaluated circMAC using full-length circRNA isoforms supported by AGO-CLIP binding-site annotations. The main pair-disjoint dataset contained 19,674 training pairs and 7,838 test pairs, with 5.7% of nucleotide positions labeled as binding sites. At the 1000-nucleotide setting, circMAC with base-pairing prediction pretraining achieved an F1-macro score of 0.762, an AUROC of 0.902 and an AUPRC of 0.545, outperforming the evaluated pretrained RNA language models. It also showed the strongest overall performance among evaluated full-length models under isoform-disjoint and BSJ-disjoint tests.
"By retaining full-length sequence context and conditioning predictions on the specific miRNA, the framework can provide more focused candidate regions for follow-up experiments," said Prof. Song.
circMAC can help computational biology researchers identify potential microRNA binding regions on circular RNA at nucleotide resolution, enabling more targeted experimental validation. In an illustrative case, it concentrated prediction signals near an annotated BSJ region of circCDYL2. However, these predictions are intended to prioritize candidate binding regions rather than establish functional interactions or clinical applications.
Overall, circMAC provides a machine-learning framework for prioritizing candidate circRNA–miRNA binding regions. By combining RNA sequence modeling, circular sequence continuity, and miRNA-specific conditioning, it could support more precise studies of RNA-mediated regulation. Further validation using independent datasets and experiments is needed before broader biological or clinical applications can be considered.
Reference
Titles of original paper: circMAC: microRNA-conditioned binding-site localization on circular RNA isoforms
Journal: Briefings in Bioinformatics
DOI: https://doi.org/10.1093/bib/bbag492
About Pusan National University
Pusan National University, located in Busan, South Korea, was founded in 1946 and is now the No. 1 national university of South Korea in research and educational competency. The multi-campus university also has other smaller campuses in Yangsan, Miryang, and Ami. The university prides itself on the principles of truth, freedom, and service and has approximately 30,000 students, 1,200 professors, and 750 faculty members. The university comprises 14 colleges (schools) and one independent division, with 103 departments in all.
Website: https://www.pusan.ac.kr/eng/Main.do
About Professor Giltae Song
Prof. Giltae Song is a professor in the School of Computer Science and Engineering at Pusan National University, South Korea, where he also serves as dean of the College of Information and Biomedical Engineering and director of the Artificial Intelligence Collaboration Hub Research Center. He joined Pusan National University in 2016. He was a postdoctoral scholar in the Department of Genetics at Stanford University School of Medicine from 2012 to 2016. He received his Ph.D. in Computer Science and Engineering from Pennsylvania State University in 2011. His research focuses on artificial intelligence, computational biology, and biomedical data analysis.
