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Efficiency of Xist-mediated silencing on autosomes is linked to chromosomal domain organisation.doc

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Efficiency of Xist-mediated silencing on autosomes is linked to chromosomal domain organisation

Efficiency of Xist-mediated silencing on autosomes is linked to chromosomal domain organisation Tang et al. Tang et al. Epigenetics Chromatin 2010, 3:10 /content/3/1/10 (7 May 2010) BioMedCentral Tang et al. Epigenetics Chromatin 2010, 3:10 /content/3/1/10 RESEARCH Open Access Efficiency of Xist-mediated silencing on autosomes Research is linked to chromosomal domain organisation Y Amy Tang1,2, Derek Huntley3, Giovanni Montana4, Andrea Cerase1,5, Tatyana B Nesterova1,5 and Neil Brockdorff*1,5 Abstract Background: 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. 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. Results: Our 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 si