Loss of p53 Causes Stochastic Aberrant X-Chromosome Inactivation and Female-Specific Neural Tube Defects
Loss of p53 Causes Stochastic Aberrant X-Chromosome Inactivation and Female-Specific Neural Tube Defects
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DOI：
10.1016/j.celrep.2019.03.048
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发表时间：
2019-04-09
期刊：
影响因子：
8.8
通讯作者：
Voss, Anne K.
中科院分区：
文献类型：
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作者：
Delbridge, Alex R. D.;Kueh, Andrew J.;Voss, Anne K.
神经管缺陷(NTD)是人类常见的出生缺陷，表现出无法解释的女性偏见。缺乏肿瘤抑制基因P53的雌性小鼠表现出不完全外显的NTDS。我们发现，促凋亡的BIM和P53的共同缺失导致了100%穿透性的、女性独有的NTDS，这使得我们能够研究P53的女性特异性功能。我们报告了女性P53(-/-)胚胎神经管样本显示X染色体标记Xist和H3K27me3不活跃的细胞较少，X连锁基因HUWE1和USP9X的双等位基因表达也随之增加。RNA测序证实，Xist基因表达减少，X连锁基因表达增加。此外，我们还发现P53直接结合了X染色体失活中心(XIC)的反应元件。综上所述，这些发现表明，P53直接激活XIC基因，否则X染色体失活存在随机失败，X染色体失活失败可能是导致神经管闭合缺陷的女性偏见的原因。
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.