CTCFL(BORIS) contributes to the transcriptional program of ovarian cancer by relaxing CTCF-mediated three-dimensional genome organization

Disruption of three-dimensional genome architecture is a major driver of cancer initiation and progression, and genetic or epigenetic alterations of CTCF- and cohesin-bound chromatin anchors are among the principal mechanisms underlying this process. These same chromatin loop anchors can also be occupied by the germ cell–specific CTCF paralog CTCFL (BORIS), which is aberrantly reactivated in multiple malignancies. Here, we show that in ovarian cancer cells, BORIS reactivation establishes a distinct transcriptional program that collapses upon BORIS knockout 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.