Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation

Györgyi Csankovszki, András Nagy, Rudolf Jaenisch

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331 Citations (Scopus)

Abstract

Xist RNA expression, methylation of CpG islands, and hypoacetylation of histone H4 are distinguishing features of inactive X chromatin. Here, we show that these silencing mechanisms act synergistically to maintain the inactive state. Xist RNA has been shown to be essential for initiation of X inactivation, but not required for maintenance. We have developed a system in which the reactivation frequency of individual X-linked genes can be assessed quantitatively. Using a conditional mutant Xist allele, we provide direct evidence for that loss of Xist RNA destabilizes the inactive state in somatic cells, leading to an increased reactivation frequency of an X-linked GFP transgene and of the endogenous hypoxanthine phosphoribosyl transferase (Hprt) gene in mouse embryonic fibroblasts. Demethylation of DNA, using 5-azadC or by introducing a mutation in Dnmtl, and inhibition of histone hypoacetylation using trichostatin A further increases reactivation in Xist mutant fibroblasts, indicating a synergistic interaction of X chromosome silencing mechanisms.

Original languageEnglish
Pages (from-to)773-783
Number of pages11
JournalJournal of Cell Biology
Volume153
Issue number4
DOIs
Publication statusPublished - 14 May 2001
Externally publishedYes

Keywords

  • DNA methylation
  • Gene silencing
  • Histone deacetylase
  • X chromosome
  • Xist gene

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