Loss of p53 causes stochastic aberrant X-chromosome inactivation and female-specific neural tube defects
- Author(s)
- Delbridge, ARD; Kueh, AJ; Ke, F; Zamudio, NM; El-Saafin, F; Jansz, N; Wang, GY; Iminitoff, M; Beck, T; Haupt, S; Hu, Y; May, RE; Whitehead, L; Tai, L; Chiang, W; Herold, MJ; Haupt, Y; Smyth, GK; Thomas, T; Blewitt, ME; Strasser, A; Voss, AK;
- Details
- Publication Year 2019-04-09,Volume 27,Issue #2,Page 442-454.e5
- Journal Title
- Cell Reports
- Publication Type
- Journal Article
- Abstract
- Neural tube defects (NTDs) are common birth defects in humans and show an unexplained female bias. Female mice lacking the tumor suppressor p53 display NTDs with incomplete penetrance. We found that the combined loss of pro-apoptotic BIM and p53 caused 100% penetrant, female-exclusive NTDs, which allowed us to investigate the female-specific functions of p53. We report that female p53(-/-) embryonic neural tube samples show fewer cells with inactive X chromosome markers Xist and H3K27me3 and a concomitant increase in biallelic expression of the X-linked genes, Huwe1 and Usp9x. Decreased Xist and increased X-linked gene expression was confirmed by RNA sequencing. Moreover, we found that p53 directly bound response elements in the X chromosome inactivation center (XIC). Together, these findings suggest p53 directly activates XIC genes, without which there is stochastic failure in X chromosome inactivation, and that X chromosome inactivation failure may underlie the female bias in neural tube closure defects.
- Publisher
- Elsevier
- Research Division(s)
- Blood Cells And Blood Cancer; Epigenetics And Development; Advanced Technology And Biology; Bioinformatics
- PubMed ID
- 30970248
- Publisher's Version
- https://doi.org/10.1016/j.celrep.2019.03.048
- Open Access at Publisher's Site
https://doi.org/10.1016/j.celrep.2019.03.048- NHMRC Grants
- NHMRC/1016701, NHMRC/1020363, NHMRC/575512, NHMRC/1081421, NHMRC/1058892, NHMRC/1054618, NHMRC/1084504, NHMRC/1051078,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2019-04-12 10:26:45
Last Modified: 2019-04-12 11:24:02