根据剂量,CDX2会影响基因调节网络,这些基因是人类胚胎外半皮发育的基础
Emily A Bulger1,2, Todd C McDevitt1,3, Benoit G Bruneau1,4,5,6,7
1Gladstone Institutes, San Francisco, CA.
bioRxiv : the preprint server for biology
|February 8, 2024
概括
CDX2基因剂量严重影响早期胚胎发育,特别是胚胎外半皮. 这项研究揭示了CDX2对细胞骨完整性和信号通路的基因进行剂量依赖的调节,这对艾伦症发育至关重要.
科学领域:
- 发展生物学 发展生物学
- 干细胞生物学 干细胞生物学
- 遗传学 是一个遗传学.
背景情况:
- 适当的基因剂量对于早期胚胎发育和胚胎外组织至关重要.
- 在活体中CDX2的损失会损害艾伦体的发育,这是营养和废物交换至关重要的结构.
研究的目的:
- 研究CDX2对控制胚胎外半皮发育的基因调控网络的剂量依赖性影响.
- 了解CDX2的剂量如何影响细胞骨完整性,细胞粘附和信号通路在开发外胚胎间皮.
主要方法:
- 在人类诱导多能干细胞 (hiPSCs) 中为CDX2生成一个等位基因序列,具有WT,异合体和同合体无基因型.
- 在2D胃类模型中对hiPSC进行分化,其次是多原子单核RNA和ATAC测序.
- 对CDX2淘汰基因表达与TBXT淘汰基因表达的比较,以确定共同调节错误的基因.
主要成果:
- 根据剂量,CDX2调节参与细胞骨完整性和粘合性的基因,包括VEGF,正规WNT和非正规WNT通路.
- 异构体CDX2表达显示了类似WT的染色质可访问性,但不能完全恢复基因表达,表明可访问性不足.
- 在CDX2和TBXT淘汰赛之间发现了共享的错误调节基因,如ANK3和ANGPT1,对细胞骨完整性和组织透性至关重要.
结论:
- CDX2剂量极大地影响胚胎外中皮的基因表达,影响细胞骨和信号通路.
- 当减少CDX2剂量时,单独的染色质可访问性不足以挽救基因表达.
- 在CDX2和TBXT功能丧失模型中,常见的错误调节基因可能解释了血管发育和全身延伸的缺陷.
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