Epigenetic deprogramming by disruption of CIZ1-RNA nuclear assemblies in early-stage breast cancers

Abstract

CIZ1 is part of the RNA-dependent supramolecular assemblies that form around the inactive X-chromosome (Xi) in female cells and smaller assemblies throughout the nucleus in both sexes. Here, we show that CIZ1 C-terminal anchor domain (AD) is elevated in human breast tumor transcriptomes, even at stage I. Elevation correlates with deprotection of chromatin and upregulation of lncRNA-containing gene clusters in ∼10 Mb regions enriched in cancer-associated genes. We modeled the effect of AD on endogenous CIZ1-Xi assemblies and observed dominant-negative interference with their reformation after mitosis, leading to abnormal assemblies similar to those in breast cancer cells, and depletion of H2AK119ub1, H3K27me3, and Xist. Consistent alterations in gene expression were evident across the genome, showing that AD-mediated interference has a destabilizing effect, likely by unscheduled exposure of underlying chromatin to modifying enzymes. The data argue for a dominant, potent, and rapid effect of CIZ1 AD that can deprogram gene expression patterns and which may predispose incipient tumors to epigenetic instability.