Female mice lacking Xist RNA show partial dosage compensation and survive to term

X chromosome inactivation (XCI) compensates for differences in X-chromosome number between male and female mammals. XCI is orchestrated by Xist RNA, whose expression in early development leads to transcriptional silencing of one X-chromosome in the female. Knockout studies have established a requirement for Xist, with inviability of female embryos that inherit an Xist deletion from the father. Here, we report that female mice lacking Xist RNA can, surprisingly, develop and survive to term. Xist-null females are born at lower frequency and are smaller at birth, but organogenesis is mostly normal. Transcriptomic analysis indicates significant overexpression of hundreds of X-linked genes across multiple tissues. Therefore, Xist-null mice can develop to term in spite of a deficiency of dosage compensation. However, the degree of X-autosomal dosage imbalance was less than anticipated (1.14- to 1.36-fold). Thus, partial dosage compensation can be achieved without Xist, supporting the idea of inherent genome balance. Nevertheless, to date, none of the mutant mice has survived beyond weaning stage. Sudden death is associated with failure of postnatal organ maturation. Our data suggest Xist-independent mechanisms of dosage compensation and demonstrate that small deviations from X-autosomal balance can have profound effects on overall fitness. Overall design: RNA-sequencing of tail-tip fibroblasts (TTFs), spleen, liver and heart tissue from Xist-null and control female mice. Sequencing performed with 50nt read length on Illumina HiSeq2000 or 2500. Data consists of 3 biological replicates for TTFs (6 datasets) and 2 biological replicates for tissues (12 datasets).

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Yang L, Kirby JE, Sunwoo H, Lee JT