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

Abstract

CIZ1 is part of the large RNA-dependent supramolecular assemblies that form around the inactive X-chromosome (Xi) in female cells, and smaller assemblies throughout the nucleus in males and females. Here we show that CIZ1 C-terminal anchor domain (AD) is elevated in primary human breast tumour transcriptomes, even at stage I. Elevation of AD correlates with deprotection of chromatin, and up-regulation of lncRNA-containing gene clusters in approximately 10Mb regions that are enriched in cancer-associated genes. We modelled the effect of ectopic AD on endogenous CIZ1-Xi assemblies and observed dominant-negative interference with their re-formation after mitosis, leading to abnormal Xi assemblies similar to those in breast cancer cells, and depletion of histone modifications H2AK119ub1 and H3K27me3. Within days consistent alterations in gene expression were evident across the genome, showing that disruption of CIZ1-RNA assemblies has a destabilizing effect, likely by unscheduled exposure of underlying chromatin to modifying enzymes. Together the data argue for a dominant, potent and rapid effect of CIZ1 AD, that can deprogram established patterns of gene expression and which may predispose incipient tumours to epigenetic instability. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/609161v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@b7a547org.highwire.dtl.DTLVardef@c404cborg.highwire.dtl.DTLVardef@116c576org.highwire.dtl.DTLVardef@1fdf8cc_HPS_FORMAT_FIGEXP M_FIG C_FIG