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. 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).X染色体失活（X chromosome inactivation, XCI）能够补偿雌雄哺乳动物间X染色体数量的差异。X染色体失活由Xist RNA调控，其在发育早期的表达会导致雌性个体中一条X染色体发生转录沉默。基因敲除研究证实了Xist的必要性：若雌性胚胎从父本遗传得到Xist缺失突变，则会无法存活。 本研究却意外发现，缺失Xist RNA的雌性小鼠仍可发育并足月存活。Xist敲除雌性小鼠的出生比例更低，出生时体型更小，但器官发生过程大多正常。转录组分析显示，在多个组织中，数百个X连锁基因均出现显著的过表达现象。因此，尽管存在剂量补偿缺陷，Xist敲除小鼠仍可发育至足月。然而，X染色体-常染色体的剂量失衡程度低于预期（1.14~1.36倍）。由此可见，无需Xist即可实现部分剂量补偿，这支持了“基因组固有平衡”的观点。但截至目前，所有突变小鼠均未能度过断奶期。其猝死与出生后器官成熟障碍相关。本研究数据揭示了不依赖Xist的剂量补偿机制，并证实X染色体-常染色体平衡的微小偏差即可对整体生存适应性产生显著影响。 本研究对Xist敲除雌性小鼠与对照雌性小鼠的尾尖成纤维细胞（tail-tip fibroblasts, TTFs）、脾脏、肝脏及心脏组织进行了RNA测序。测序采用Illumina HiSeq2000或2500平台，读长为50nt。数据集包含尾尖成纤维细胞的3次生物学重复（共6个数据集）以及组织样本的2次生物学重复（共12个数据集）。