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

机译：Xist介导的常染色体沉默的效率与染色体域组织有关

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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 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. Conclusions This 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.
机译：背景X染色体失活是哺乳动物用来平衡XX雌性相对于XY雄性的XX雌性中X连锁基因剂量的机制，是由顺式作用非编码RNA Xist的全染色体定位触发的。 Xist RNA扩散和Xist依赖沉默的机制了解甚少。大量证据表明，在X染色体上沉默比在常染色体上更有效，这导致人们认为X染色体已获得了促进沉默传播的序列。 LINE-1（L1）重复序列在X染色体上相对富集，已被提议作为这些序列的候选者。为了确定有效沉默的要求，我们分析了包括L1重复在内的染色体特征之间的关系，以及位于三个不同常染色体之一上的携带可诱导Xist转基因的细胞系中沉默的程度。结果我们的结果表明，将染色体组织成富含基因的大域和富含L1的域是决定沉默效率的关键因素。特别地，位于低L1密度的大型基因富集域中的基因相对抗Xist介导的沉默，而位于高L1密度的基因贫域中的基因则更有效地沉默。在诱导Xist RNA表达后不久就观察到了这些效应，表明染色体结构域影响了沉默的建立而非长期维持。 X染色体和某些常染色体仅具有小的富含基因的L1缺失结构域，我们建议这可以赋予相对有效的染色体范围内沉默的能力。结论这项研究提供了对有效Xist介导的沉默的要求的见解，并特别确定了将染色体组织成富含基因的L1缺失和基因贫乏的L1密集域，这是对Xist介导的沉默传播能力的主要影响。以连续方式顺式

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