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

Abstract

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.

• Authors: J Mauro Calabrese, Wei Sun, Lingyun Song, Joshua W Mugford, Lucy Williams, Della Yee, Joshua Starmer, Piotr Mieczkowski, Gregory E Crawford, Terry Magnuson
• Journal: Cell (Cell) Vol. 151 Issue 5 Pg. 951-63 (Nov 21 2012) ISSN: 1097-4172 [Electronic] United States
• PMID: 23178118 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• 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, metabolism)
• Trophoblasts (cytology)
• X Chromosome Inactivation