在Atf4位点的转录读透抑制Rps19bp1并损害心脏发育.
Zengming Zhang1, Tongbin Wu2, Zeyu Chen1
1Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Cardiovascular research
|November 17, 2025
概括
心脏发育依赖于RPS19BP1,而不是ATF4. 删除Atf4 polyA信号导致阅读,降低RPS19BP1的调节,并导致心脏缺陷. 这突出了以前的Atf4淘汰赛模型中的潜在工件.
科学领域:
- 心血管生物学 心血管生物学
- 分子遗传学 分子遗传学
- 转录条例 转录条例 转录条例
背景情况:
- 激活转录因子4 (ATF4) 是各种生理和病理条件的关键调节者.
- 以前的研究将ATF4与心脏病中的心肌细胞死亡联系起来,但其在心肌细胞发育中的作用尚不清楚.
研究的目的:
- 研究ATF4在心肌细胞发育中的作用.
- 为了生成和分析新的小鼠模型来研究心脏中的ATF4功能.
主要方法:
- 产生了心肌细胞特异性和全球Atf4淘汰赛小鼠模型.
- 创建了特定于心肌细胞的Rps19bp1删除模型.
- 对心脏表型进行了详细的形态和分子分析.
主要成果:
- 心肌细胞特异性Atf4淘汰与多A删除 (Atf4cKO(e2/3/pA)) 导致严重的心脏缺陷和胚胎致死性.
- 这些缺陷被归因于Rps19bp1下调,这是由于从删除的Atf4 polyA信号中转录读取的原因.
- 没有polyA信号删除的Atf4淘汰模型 (Atf47del/7del,Atf41ins/1ins) 显示了正常的心脏发育.
- 特定于心肌细胞的Rps19bp1删除重复了在Atf4cKO(e2/3/pA) 小鼠中观察到的心脏缺陷.
结论:
- 在Atf4cKO(e2/3/pA) 小鼠中的心脏表型是由于Rps19bp1下调导致的,而不是ATF4功能的丧失.
- 转录读透和Rps19bp1下调可能是先前报道的Atf4淘汰赛研究中的混因素.
- RPS19BP1在心脏发育中起着至关重要的作用,基因模型研究中必须考虑依赖于位置的转录干扰机制.
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