Human Molecular Genetics, Vol 5, 1345-1353, Copyright © 1996 by Oxford University Press
RS Hansen, TK Canfield, AD Fjeld and SM Gartler
Cytosine methylation at promoter regions and late replication timing have
both been implicated in the regulation of genes subject to X chromosome
inactivation. Reported here are studies of X-linked gene replication in
normal male and female cells as well as in cell hybrids that contain either
a normal active X, a normal inactive X, or an inactive X chromosome that
has been treated with the demethylating agent, 5-azacytidine (5aC). The
relationship between replication timing and transcriptional activity was
examined for XIST, XPCT, PGK1, HPRT, F9, FMR1, IDS, and G6PD, and earlier
replication was generally found to be associated with increased
transcriptional activity. The HPRT and G6PD genes in an untreated inactive
X hybrid were among the few exceptions to this correlation in that they
remain inactive, yet replicate earlier than their inactive X alleles
present in normal human diploid cells. This condition of earlier
replication timing may contribute to the high rates of 5aC-induced
reactivation for HPRT and G6PD in this hybrid relative to other inactive X
hybrids. Other anomalous cases include 5aC-induced advances in replication
time for genes such as XIST and F9 whose transcription was unaltered by
treatment. These and other data support a model for regulation of X-
inactivated genes that involves at least two levels of control: (i) large
chromosomal domains are placed into a transcriptionally nonpermissive state
by late replication and (ii) transcription is blocked at the local level by
promoter methylation. In addition, our observations of continued XIST
expression in 5aC-treated hybrids with reactivated genes indicates that
such expression is not sufficient for the maintenance of X inactivation.
ARTICLES
Role of late replication timing in the silencing of X-linked genes
Department of Medicine, University of Washington, Seattle 98195, USA.
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