Synergism of Xist Rna, DNA Methylation, and Histone Hypoacetylation in Maintaining X Chromosome Inactivation

doi:10.1083/jcb.153.4.773

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Published online 14 May 2001. doi:10.1083/jcb.153.4.773

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© The Rockefeller University Press, 0021-9525/2001//773 $5.00
The Journal of Cell Biology, Volume 153, Number 4, , 2001 773-784

Original Article

Synergism of Xist Rna, DNA Methylation, and Histone Hypoacetylation in Maintaining X Chromosome Inactivation

Györgyi Csankovszki^a, András Nagy^b, and Rudolf Jaenisch^a

^a Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142
^b Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142.(617) 258-6505(617) 258-5186

jaenisch{at}wi.mit.edu

Xist RNA expression, methylation of CpG islands, and hypoacetylationof histone H4 are distinguishing features of inactive X chromatin.Here, we show that these silencing mechanisms act synergisticallyto maintain the inactive state. Xist RNA has been shown to beessential for initiation of X inactivation, but not requiredfor maintenance. We have developed a system in which the reactivationfrequency of individual X-linked genes can be assessed quantitatively.Using a conditional mutant Xist allele, we provide direct evidencefor that loss of Xist RNA destabilizes the inactive state insomatic cells, leading to an increased reactivation frequencyof an X-linked GFP transgene and of the endogenous hypoxanthinephosphoribosyl transferase (Hprt) gene in mouse embryonic fibroblasts.Demethylation of DNA, using 5-azadC or by introducing a mutationin Dnmt1, and inhibition of histone hypoacetylation using trichostatinA further increases reactivation in Xist mutant fibroblasts,indicating a synergistic interaction of X chromosome silencingmechanisms.

Key Words: X chromosome • Xist gene • DNA methylation • histone deacetylase • gene silencing

Abbreviations used in this paper: GFP, green fluorescent protein;HAT, hypoxanthine/aminopterin/thymidine; Hprt, hypoxanthinephosphoribosyl transferase; IAP, intracisternal A particle;ICF, immunodeficiency centromeric instability facial anomalies;TSA, trichostatin A; Xa, active X; Xi, inactive X.

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