Traver, M. | Search bioRxiv

bioRxiv2026

The CTCF Paralog BORIS Contributes to the Ovarian Cancer Transcriptional Program by Relaxing CTCF-mediated 3D Genome Organization

Disruption of three-dimensional genome architecture is a major driver of cancer initiation and progression, frequently arising from genetic and epigenetic alterations at CTCF- and cohesin-bound chromatin anchors. These same chromatin loop anchors can also be occupied by the germ cell-specific CTCF paralog CTCFL (BORIS), which is aberrantly activated in multiple malignancies. Here, we show that in ovarian cancer cells, BORIS activation establishes a distinct transcriptional program that collapses following loss of BORIS chromatin binding and is accompanied by widespread changes in CTCF and cohesin occupancy, histone modifications, and chromatin accessibility. These BORIS-dependent transcriptional alterations occur in long-range genomic clusters, resulting in the coordinated activation or repression of neighboring genes, including hormonally regulated gene families. BORIS loss also increases topologically associating domain (TAD) insulation, strengthens A/B compartment segregation and chromatin loop interactions, and results in a more compact and constrained chromatin architecture. Together, our findings suggest that aberrant BORIS activation promotes transcriptional reprogramming by weakening CTCF-mediated chromatin insulation and relaxing three-dimensional genome organization in ovarian cancer. SignificanceHigh-grade serous ovarian carcinoma, the most common subtype of ovarian cancer, remains one of the deadliest gynecological malignancies because of its late diagnosis, extensive genomic instability, and frequent therapeutic resistance. The lack of reliable biomarkers for early detection underscores the need to identify new molecular drivers of disease initiation and progression. Here, we show that the germline-specific gene CTCFL (BORIS) is aberrantly activated in high-grade serous ovarian carcinoma, where it remodels transcriptional, epigenetic, and three-dimensional genome organization by occupying CTCF-bound chromatin loop anchors and weakening CTCF-mediated chromatin insulation. These findings identify BORIS as a key regulator of transcriptional reprogramming in ovarian cancer and support its further investigation as both a prognostic biomarker and a potential therapeutic target.

cancer biology↗

bioRxiv2024

Progressive heterogeneity of enlarged and irregularly shaped apicoplasts in P. falciparum persister blood stages after drug treatment

Morphological modifications and shifts in organelle relationships are hallmarks of dormancy in eukaryotic cells. Communications between altered mitochondria and nuclei are associated with metabolic quiescence of cancer cells that can survive chemotherapy. In plants, changes in the pathways between nuclei, mitochondria, and chloroplasts are associated with cold stress and bud dormancy. Plasmodium falciparum parasites, the deadliest agent of malaria in humans, contain a chloroplast-like organelle (apicoplast) derived from an ancient photosynthetic symbiont. Antimalarial treatments can fail because a small fraction of the blood stage parasites enter dormancy and recrudesce after drug exposure. Altered mitochondrial-nuclear interactions in these persisters have been described for P. falciparum, but interactions of the apicoplast remained to be characterized. In the present study, we examined the apicoplasts of persisters obtained after exposure to dihydroartemisinin (a first-line antimalarial drug) followed by sorbitol treatment, or after exposure to sorbitol treatment alone. As previously observed, the mitochondrion of persisters was consistently enlarged and in close association with the nucleus. In contrast, the apicoplast varied from compact and oblate, like those of active ring stage parasites, to enlarged and irregularly shaped. Enlarged apicoplasts became more prevalent later in dormancy, but regular size apicoplasts subsequently predominated in actively replicating recrudescent parasites. All three organelles, nucleus, mitochondrion, and apicoplast, became closer during dormancy. Understanding their relationships in erythrocytic-stage persisters may lead to new strategies to prevent recrudescences and protect the future of malaria chemotherapy. Significance StatementDormancy of blood-stage malaria parasites (as persister forms) frequently undermines treatment and may facilitate the evolution of drug resistance. Here, we examine changes that occur in dormancy with two P. falciparum organelles relative to the nucleus: the mitochondrion and the plastid-like apicoplast. As previously reported, the mitochondrion of persisters is consistently enlarged, irregularly shaped, and shifted into close apposition with the nucleus. However, apicoplasts exhibit a greater variety of shapes, volumes, and relative positioning during dormancy: some persisters maintain a regular appearing apicoplast, while others show dramatically altered apicoplasts, reminiscent of the chloroplast swelling and degradation that occurs with death from reactive oxygen species in various plant cells. Improved understanding of these processes will support new approaches in antimalarial chemotherapy.

microbiology↗