Maintenance of epigenetic landscape requires CIZ1 and is corrupted in differentiated fibroblasts in long-term culture

Nat Commun. 2019 Jan 28;10(1):460. doi: 10.1038/s41467-018-08072-2.

Abstract

The inactive X chromosome (Xi) serves as a model for establishment and maintenance of repressed chromatin and the function of polycomb repressive complexes (PRC1/2). Here we show that Xi transiently relocates from the nuclear periphery towards the interior during its replication, in a process dependent on CIZ1. Compromised relocation of Xi in CIZ1-null primary mouse embryonic fibroblasts is accompanied by loss of PRC-mediated H2AK119Ub1 and H3K27me3, increased solubility of PRC2 catalytic subunit EZH2, and genome-wide deregulation of polycomb-regulated genes. Xi position in S phase is also corrupted in cells adapted to long-term culture (WT or CIZ1-null), and also accompanied by specific changes in EZH2 and its targets. The data are consistent with the idea that chromatin relocation during S phase contributes to maintenance of epigenetic landscape in primary cells, and that elevated soluble EZH2 is part of an error-prone mechanism by which modifying enzyme meets template when chromatin relocation is compromised.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Cells, Cultured
  • Chromatin / genetics
  • Chromatin / metabolism
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Epigenesis, Genetic*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Gene Expression Profiling
  • Histones / metabolism
  • Methylation
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • S Phase / genetics
  • Time Factors

Substances

  • Chromatin
  • Ciz1 protein, mouse
  • Histones
  • Nuclear Proteins
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse