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

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.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.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 additionally highlighted that autosomal genes in cis with the Xic are inactivated less efficiently than normal X-linked genes [1-4]. This latter observation was suggested to be due to inefficient propagation or maintenance of X inactivation. More recently it has been shown that chromosome coating by X inactive specific transcript (Xist) RNA is the primary cis-acting trigger for X inactivation [5-7], and moreover that expression of Xist transgenes randomly integrated on mouse autosomes leads to coating and chromosome-wide silencing [8,9]. However, in other studies it has been shown that Xist RNA coating and associated silencing is compromised on autosomal chromatin in specific X; autosome rearrangements [10-14].The relative insensitivity of autosoma