转录因子ZNF469调节肝纤维化中的原蛋白生产
Sebastian Steinhauser1, David Estoppey1, Dennis P Buehler2
1Novartis Biomedical Research, Basel, Switzerland.
bioRxiv : the preprint server for biology
|May 7, 2024
概括
研究人员确定ZNF469是肝细胞中原蛋白生产的关键调节者. 这一发现揭示了非酒精性脂肪性肝病 (NAFLD) 导致肝纤维化的机制.
科学领域:
- 分子生物学分子生物学
- 肝病学 肝病学是一种肝病学.
- 基因组学和表观基因组学
背景情况:
- 非酒精性脂肪肝 (NAFLD) 影响全球三分之一的人口,其特点是肝脏脂肪积累.
- 肝纤维化是NAFLD进展的结果,涉及原沉积,是死亡的主要原因.
- 识别纤维化转录调节剂对于理解和治疗NAFLD至关重要.
研究的目的:
- 确定在非酒精性脂肪性肝病 (NAFLD) 中调节纤维化的转录因子 (TF).
- 调查ZNF469在肝脏星状细胞 (HSC) 中的原生产和矩阵稳态中的作用.
主要方法:
- 计算推断转录因子活性使用匹配的转录和表观基因组数据从108个人类肝脏活检在NAFLD频谱.
- 基于CRISPR的基因淘汰屏幕,用于初级人类肝星细胞 (HSC) 中的前100个TF.
- 功能增益和丧失研究,以验证ZNF469对原和矩阵平衡基因的调节作用.
主要成果:
- 鉴定ZNF469是人类肝脏恒星细胞 (HSC) 中原表达的调节者.
- ZNF469直接与基因体和调节元件结合,控制原基因和参与矩阵平衡的基因.
- 综合实验验证的多原子分析证实了ZNF469作为HSC中的原蛋白的转录调节器的功能.
结论:
- ZNF469是与NAFLD相关的肝纤维化以前未被识别的决定因素.
- 向ZNF469可能为缓解NAFLD相关的肝纤维化提供一种新的治疗策略.
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