The nuclear matrix protein CIZ1 facilitates localization of Xist RNA to the inactive X-chromosome territory

• Published in: Genes & development Vol. 31; no. 9; pp. 876 - 888
• Main Authors: Ridings-Figueroa, Rebeca, Stewart, Emma R., Nesterova, Tatyana B., Coker, Heather, Pintacuda, Greta, Godwin, Jonathan, Wilson, Rose, Haslam, Aidan, Lilley, Fred, Ruigrok, Renate, Bageghni, Sumia A., Albadrani, Ghadeer, Mansfield, William, Roulson, Jo-An, Brockdorff, Neil, Ainscough, Justin F.X., Coverley, Dawn
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.05.2017
• Subjects: Animals; Cell Differentiation; Cells, Cultured; Embryo, Mammalian - metabolism; Embryo, Mammalian - pathology; Embryonic Stem Cells - metabolism; Embryonic Stem Cells - pathology; Female; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Expression Regulation; Humans; Lymphoproliferative Disorders - genetics; Lymphoproliferative Disorders - metabolism; Lymphoproliferative Disorders - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Nuclear Proteins - physiology; Research Paper; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Sex Characteristics; X Chromosome - genetics; X Chromosome - metabolism; X Chromosome Inactivation; CIZ1; lymphoproliferative disorder; Xist; nuclear matrix; X-chromosome inactivation
• ISSN: 0890-9369; 1549-5477; 1549-5477
• DOI: 10.1101/gad.295907.117

The nuclear matrix protein Cip1-interacting zinc finger protein 1 (CIZ1) promotes DNA replication in association with cyclins and has been linked to adult and pediatric cancers. Here we show that CIZ1 is highly enriched on the inactive X chromosome (Xi) in mouse and human female cells and is retained by interaction with the RNA-dependent nuclear matrix. CIZ1 is recruited to Xi in response to expression of X inactive-specific transcript (Xist) RNA during the earliest stages of X inactivation in embryonic stem cells and is dependent on the C-terminal nuclear matrix anchor domain of CIZ1 and the E repeats of Xist . CIZ1-null mice, although viable, display fully penetrant female-specific lymphoproliferative disorder. Interestingly, in mouse embryonic fibroblast cells derived from CIZ1-null embryos, Xist RNA localization is disrupted, being highly dispersed through the nucleoplasm rather than focal. Focal localization is reinstated following re-expression of CIZ1. Focal localization of Xist RNA is also disrupted in activated B and T cells isolated from CIZ1-null animals, suggesting a possible explanation for female-specific lymphoproliferative disorder. Together, these findings suggest that CIZ1 has an essential role in anchoring Xist to the nuclear matrix in specific somatic lineages.