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Widespread organ tolerance to Xist loss and X reactivation except under chronic stress in the gut.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Feb 25; Vol. 117 (8), pp. 4262-4272. Date of Electronic Publication: 2020 Feb 10. - Publication Year :
- 2020
-
Abstract
- Long thought to be dispensable after establishing X chromosome inactivation (XCI), Xist RNA is now known to also maintain the inactive X (Xi). To what extent somatic X reactivation causes physiological abnormalities is an active area of inquiry. Here, we use multiple mouse models to investigate in vivo consequences. First, when Xist is deleted systemically in post-XCI embryonic cells using the Meox2-Cre driver, female pups exhibit no morbidity or mortality despite partial X reactivation. Second, when Xist is conditionally deleted in epithelial cells using Keratin14-Cre or in B cells using CD19-Cre, female mice have a normal life span without obvious illness. Third, when Xist is deleted in gut using Villin-Cre, female mice remain healthy despite significant X-autosome dosage imbalance. Finally, when the gut is acutely stressed by azoxymethane/dextran sulfate (AOM/DSS) exposure, both Xist -deleted and wild-type mice develop gastrointestinal tumors. Intriguingly, however, under prolonged stress, mutant mice develop larger tumors and have a higher tumor burden. The effect is female specific. Altogether, these observations reveal a surprising systemic tolerance to Xist loss but importantly reveal that Xist and XCI are protective to females during chronic stress.<br />Competing Interests: Competing interest statement: J.T.L. is a cofounder of Translate Bio and Fulcrum Therapeutics, and an advisor to Skyhawk Therapeutics. To our knowledge, none of the companies is presently working on Xi reactivation.
- Subjects :
- Animals
Female
Gastrointestinal Neoplasms etiology
Gastrointestinal Neoplasms genetics
Gastrointestinal Neoplasms metabolism
Gastrointestinal Tract metabolism
Genetic Diseases, X-Linked complications
Genetic Diseases, X-Linked metabolism
Humans
Male
Mice
RNA, Long Noncoding metabolism
Stress, Physiological
Tumor Burden
X Chromosome Inactivation
Gastrointestinal Neoplasms physiopathology
Genetic Diseases, X-Linked genetics
Genetic Diseases, X-Linked microbiology
RNA, Long Noncoding genetics
X Chromosome genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 117
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 32041873
- Full Text :
- https://doi.org/10.1073/pnas.1917203117