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

Genes Dev. 2017 May 1;31(9):876-888. doi: 10.1101/gad.295907.117. Epub 2017 May 25.

Abstract

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.

Keywords: CIZ1; X-chromosome inactivation; Xist; lymphoproliferative disorder; nuclear matrix.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Sex Characteristics
  • X Chromosome / genetics
  • X Chromosome / metabolism*
  • X Chromosome Inactivation*

Substances

  • Ciz1 protein, mouse
  • Nuclear Proteins
  • RNA, Long Noncoding
  • XIST non-coding RNA