Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2019-04, Vol.27 (2), p.442-454.e5

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. [Display omitted] •p53/Bim double knockout causes fully penetrant, female-specific neural tube defects•p53 binds to sites in the X chromosome inactivation center•Loss of p53 results in marked reduction of Xist RNA levels•Absence of p53 causes biallelic expression of X chromosome genes The molecular mechanisms underlying the female bias of neural tube defects are currently unclear. Delbridge et al. present evidence that p53 is required for normal Xist expression and X chromosome inactivation and show in two models that partial failure of X chromosome inactivation is associated with female-biased neural tube defects.