Ovarian circular DNA shows reduced abundance in PCOS rat model

Researchers have mapped the landscape of extrachromosomal circular DNA (eccDNA) in the ovaries of rats with polycystic ovary syndrome (PCOS), finding that these small ring-shaped DNA molecules are less abundant in the polycystic ovary than in healthy controls. The study, published in Biology Direct, offers an initial characterization of a class of genomic elements that has been increasingly recognized as a dynamic player in gene regulation, but whose role in PCOS had remained largely unknown.

The team used a well-established animal model in which female Sprague-Dawley rats were assigned to either a control group or a PCOS group, with the syndrome induced by administration of dehydroepiandrosterone. Model establishment was confirmed by classic hallmarks: abnormal follicular development in the ovaries, altered sex hormone levels, and irregular estrous cycles. Ovarian tissue from both groups was then subjected to circle sequencing, a method designed to enrich and read out circular DNA molecules that escape the linear genome.

The sequencing effort identified 15,207 eccDNA molecules representing 13,762 distinct types. Overall abundance of these circular molecules was reduced in the ovaries of PCOS rats compared with controls. Among them, 263 circular DNAs showed differential abundance between the two groups: 260 were small eccDNAs, while 3 were larger circular molecules. This shift in the circular DNA repertoire suggests that the polycystic ovarian environment is accompanied by measurable changes in how these elements are generated or maintained.

One chromosome stood out in the analysis. Chromosome 12 was the only chromosome showing significant differences in both the chromosome-wise count distribution and the chromosome-normalized density of eccDNA after Benjamini–Hochberg correction for multiple testing, with both comparisons reaching P < 0.001. This pattern points to a non-random, chromosome-specific alteration in circular DNA production in the PCOS ovary rather than a uniform genome-wide shift.

The structural features of the molecules also carried informative signatures. Length distributions were bimodal in both groups, with peaks at 208 and 368 base pairs in controls and at 212 and 359 base pairs in the PCOS group, indicating that circular DNA in the ovary arises preferentially at two characteristic size classes.

Genomic overlap analyses showed that the eccDNA molecules intersected with annotated genes, non-coding RNAs, circular RNAs, and transposable elements. Functional enrichment of the associated genes highlighted synaptic structures, iron ion homeostasis, cell junction-related processes, and the T cell receptor signaling pathway. The overlap with multiple classes of non-coding RNAs, particularly long non-coding RNAs, led the authors to suggest potential RNA-mediated regulatory mechanisms, though these remain hypotheses for future work rather than demonstrated pathways.

To validate the sequencing findings, the researchers turned to two complementary approaches. Transmission electron microscopy revealed ring-shaped, circular DNA-like structures in the samples, providing direct visual evidence that the molecules exist as closed circles. Endpoint polymerase chain reaction on selected candidate molecules confirmed relative abundance patterns consistent with the sequencing results, supporting the reliability of the differential abundance calls between the PCOS and control groups.

The authors are careful to frame the work as preliminary. In their conclusions, they describe the study as an initial characterization of eccDNA profiles in PCOS rat ovaries, revealing reduced abundance, altered genomic features, and enrichment of associated genes in T-cell receptor signaling, and they position the findings as evidence supporting further mechanistic and clinical investigation rather than as proof of causation. Because the study was conducted in a hormone-induced rat model, the results cannot be directly extended to human patients without additional studies.

If altered eccDNA profiles are confirmed in human ovarian tissue, these circular molecules, or the genes and non-coding RNAs they intersect, could eventually serve as research targets for probing how the polycystic ovary regulates its genome. For now, the study establishes a reference map of ovarian circular DNA in a PCOS model and provides the methodological groundwork for the next generation of experiments.

Subject of Research: Extrachromosomal circular DNA profiles in the ovaries of a rat model of polycystic ovary syndrome

Article Title: Identification and characterization of ovarian extrachromosomal circular deoxyribonucleic acid in rats with polycystic ovary syndrome

Article References: Chen, Z., Song, H., Deng, J.-J., Wu, Y.-X., Liu, T.-J., Xia, M., Lin, A.-L., Chen, C., Feng, J.-Y., & Yang, H. (2026). Identification and characterization of ovarian extrachromosomal circular deoxyribonucleic acid in rats with polycystic ovary syndrome. Biology Direct. https://doi.org/10.1186/s13062-026-01011-y

Image Credits: AI Generated

DOI: 10.1186/s13062-026-01011-y

Keywords: eccDNA, PCOS, polycystic ovary syndrome, circle sequencing, rat model, ovary, chromosome 12, non-coding RNA, T cell receptor signaling, transposable elements, transmission electron microscopy, Biology Direct