Journal article

Loss of p53 Causes Stochastic Aberrant X-Chromosome Inactivation and Female-Specific Neural Tube Defects

Alex RD Delbridge, Andrew J Kueh, Francine Ke, Natasha M Zamudio, Farrah El-Saafin, Natasha Jansz, Gao-Yuan Wang, Megan Iminitoff, Tamara Beck, Sue Haupt, Yifang Hu, Rose E May, Lachlan Whitehead, Lin Tai, William Chiang, Marco J Herold, Ygal Haupt, Gordon K Smyth, Tim Thomas, Marnie E Blewitt Show all

CELL REPORTS | CELL PRESS | Published : 2019

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 dir..

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Grants

Awarded by National Health and Medical Research Council


Awarded by Leukemia and Lymphoma Society (SCOR grant)


Awarded by NHMRC


Awarded by National Breast Cancer Foundation


Funding Acknowledgements

We thank Drs. C. Scott, T. Jacks, A. Villunger, T. Kaufmann, D. C. S. Huang, S.J. Korsmeyer, C. Thompson, J.M. Adams, and P. Bouillet for gifts of mice; Moshe Oren, Antonio Constanzo, and Giovanni Blandino for provision of reagents; K. Humphries, K. Walker, E. Lanera, J. Mansheim, G. Siciliano, S. O'Connor, K. Trueman, G. Dabrowski, and K. Vella for expert animal care; and B. Helbert, H. Ierino, K. Mackwell, and C. Young for mouse genotyping. C. Scott was responsible for the initial mating of the Bim<SUP>-/-</SUP> and p53<SUP>-/-</SUP> strains and generously bequeathed this colony. This work was supported by grants and fellowships from the Cancer Council of Victoria (A.R.D.D., Sydney Parker Smith Postdoctoral Research Fellowship), the National Health and Medical Research Council (program grant no. 1016701; SPRF Fellowship 1020363 to A. S.; SRF Fellowships 575512 and 1081421 to A.K.V.; PRF Fellowship 1058892 and program grant 1054618 to G. K. S.; project grants 1051078 and 1084504), the Leukemia and Lymphoma Society (SCOR grant no. 7001-13), the estate of Anthony (Toni) Redstone OAM, Australian Postgraduate Awards (A.R.D.D., N.J., and F.E.-S.), The Bellberry-Viertel Senior Medical Research Fellowship (M.E.B.) and Cancer Therapeutics CRC Top-up Scholarship (A.R.D.D.), the Peter MacCallum Cancer Foundation (S. H.) and NHMRC 1123057, and National Breast Cancer Foundation IN-16-042 (Y. Haupt). This work was made possible by operational infrastructure grants through the Australian Government IRISS and the Victorian State Government OIS.