Abstract
BackgroundX chromosome inactivation, the mechanism used by mammals to equalise dosage of X-linked genes in XX females relative to XY males, is triggered by chromosome-wide localisation of a cis-acting non-coding RNA, Xist. The mechanism of Xist RNA spreading and Xist-dependent silencing is poorly understood. A large body of evidence indicates that silencing is more efficient on the X chromosome than on autosomes, leading to the idea that the X chromosome has acquired sequences that facilitate propagation of silencing. LINE-1 (L1) repeats are relatively enriched on the X chromosome and have been proposed as candidates for these sequences. To determine the requirements for efficient silencing we have analysed the relationship of chromosome features, including L1 repeats, and the extent of silencing in cell lines carrying inducible Xist transgenes located on one of three different autosomes.ResultsOur results show that the organisation of the chromosome into large gene-rich and L1-rich domains is a key determinant of silencing efficiency. Specifically genes located in large gene-rich domains with low L1 density are relatively resistant to Xist-mediated silencing whereas genes located in gene-poor domains with high L1 density are silenced more efficiently. These effects are observed shortly after induction of Xist RNA expression, suggesting that chromosomal domain organisation influences establishment rather than long-term maintenance of silencing. The X chromosome and some autosomes have only small gene-rich L1-depleted domains and we suggest that this could confer the capacity for relatively efficient chromosome-wide silencing.ConclusionsThis study provides insight into the requirements for efficient Xist mediated silencing and specifically identifies organisation of the chromosome into gene-rich L1-depleted and gene-poor L1-dense domains as a major influence on the ability of Xist-mediated silencing to be propagated in a continuous manner in cis.
Highlights
X chromosome inactivation, the mechanism used by mammals to equalise dosage of X-linked genes in XX females relative to XY males, is triggered by chromosome-wide localisation of a cis-acting non-coding RNA, X inactive specific transcript (Xist)
Xist-mediated silencing of genes on mouse chromosomes 3, 12 and 17 To identify cis-acting features associated with inefficient silencing on autosomes we carried out genome-wide analysis of gene expression in mouse embryonic stem (ES) cell lines expressing an autosomal doxycyclineinducible Xist transgene
We focused our analysis on three independent cell lines, 8A, 12B and 3E, in which the transgene integration site was mapped to chromosomes 3, 12 and 17, respectively (Figure 1a)
Summary
X chromosome inactivation, the mechanism used by mammals to equalise dosage of X-linked genes in XX females relative to XY males, is triggered by chromosome-wide localisation of a cis-acting non-coding RNA, Xist. Classical studies on X; autosome rearrangements have demonstrated that X inactivation propagates in cis from a single locus on the X chromosome, the X inactivation centre (Xic), and highlighted that autosomal genes in cis with the Xic are inactivated less efficiently than normal X-linked genes [1,2,3,4]. This latter observation was suggested to be due to inefficient propagation or maintenance of X inactivation.
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