Site-specific silencing of regulatory elements as a mechanism of X inactivation

Cell. 2012 Nov 21;151(5):951-63. doi: 10.1016/j.cell.2012.10.037.


The inactive X chromosome's (Xi) physical territory is microscopically devoid of transcriptional hallmarks and enriched in silencing-associated modifications. How these microscopic signatures relate to specific Xi sequences is unknown. Therefore, we profiled Xi gene expression and chromatin states at high resolution via allele-specific sequencing in mouse trophoblast stem cells. Most notably, X-inactivated transcription start sites harbored distinct epigenetic signatures relative to surrounding Xi DNA. These sites displayed H3-lysine27-trimethylation enrichment and DNaseI hypersensitivity, similar to autosomal Polycomb targets, yet excluded Pol II and other transcriptional hallmarks, similar to nontranscribed genes. CTCF bound X-inactivated and escaping genes, irrespective of measured chromatin boundaries. Escape from X inactivation occurred within, and X inactivation was maintained exterior to, the area encompassed by Xist in cells subject to imprinted and random X inactivation. The data support a model whereby inactivation of specific regulatory elements, rather than a simple chromosome-wide separation from transcription machinery, governs gene silencing over the Xi.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCCTC-Binding Factor
  • Chromatin / metabolism
  • Deoxyribonuclease I / metabolism
  • Gene Silencing*
  • Histone Code
  • Long Interspersed Nucleotide Elements
  • Mice
  • Polycomb-Group Proteins / metabolism
  • RNA Polymerase II / metabolism
  • Regulatory Elements, Transcriptional*
  • Repressor Proteins / metabolism
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Trophoblasts / cytology
  • X Chromosome Inactivation*


  • CCCTC-Binding Factor
  • Chromatin
  • Ctcf protein, mouse
  • Polycomb-Group Proteins
  • Repressor Proteins
  • RNA Polymerase II
  • Deoxyribonuclease I

Associated data

  • GEO/GSE39406