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

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.

CIZ1 in Xist seeded assemblies at the inactive X chromosome.

There is growing evidence that X-chromosome inactivation is driven by phase-separated supramolecular assemblies. However, among the many proteins recruited to the inactive X chromosome by long non-coding RNA, so far only a minority (CIZ1, CELF1, SPEN, TDP-43, MATR3, PTBP1, PCGF5) have been shown to form -seeded protein assemblies, and of these most have not been analyzed in detail. With focus on CIZ1, here we describe 1) the contribution of intrinsically disordered regions in RNA-dependent protein assembly formation at the inactive X chromosome, and 2) enrichment, distribution, and function of proteins within -seeded assemblies.

Chromatin Dynamics During Entry to Quiescence and Compromised Functionality in Cancer Cells.

Quiescence is a vital cellular state where cells can reversibly exit the cell cycle and cease proliferation in unfavourable conditions. Cells can undergo multiple transitions in and out of quiescence during their lifetime, and an imbalance in this highly regulated process can promote tumorigenesis and disease. The nucleus experiences vast changes during entry to quiescence, including changes in gene expression and a reduction in size due to increased chromatin compaction.

Prion-like domains drive CIZ1 assembly formation at the inactive X chromosome.

CIZ1 forms large assemblies at the inactive X chromosome (Xi) in female fibroblasts in an Xist lncRNA-dependent manner and is required for accurate maintenance of polycomb targets genome-wide. Here we address requirements for assembly formation and show that CIZ1 undergoes two direct interactions with Xist, via independent N- and C-terminal domains. Interaction with Xist, assembly at Xi, and complexity of self-assemblies formed in vitro are modulated by two alternatively spliced glutamine-rich prion-like domains (PLD1 and 2).