title: Female mice lacking Xist RNA show partial dosage compensation and survive to term.
abstract: 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-fold 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.
authors.affiliation: Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA;
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Kirby
authors.affiliation: Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA;
authors.forename: Hongjae
authors.initials: H
authors.lastname: Sunwoo
authors.affiliation: Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA;
authors.forename: Jeannie T
authors.initials: JT
authors.lastname: Lee
mesh_terms: D000818:Animals; D004303:Dosage Compensation, Genetic / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D009206:Myocardium / Q000473:pathology; D062085:RNA, Long Noncoding / Q000235:genetics*; D017384:Sequence Deletion; D013154:Spleen / Q000473:pathology; D016019:Survival Analysis; D014960:X Chromosome / Q000235:genetics; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: D062085:RNA, Long Noncoding; C077885:XIST non-coding RNA
keywords: X inactivation; Xist; dosage compensation; genome balance; inverse effect; knockout mouse; transcriptomics