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活动依赖神经保护蛋白招募HP1和CHD4来控制特定基因

Veronika Ostapcuk^1,2, Fabio Mohn¹, Sarah H Carl^1,3

¹Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

|May 26, 2018

概括

活动依赖神经保护蛋白 (ADNP) 与CHD4和HP1形成复合体,以调节基因表达和细胞命运. 这个复杂的

科学领域:

分子生物学
发育生物学
遗传学

背景情况:

在ADNP中发生的新突变导致Helsmoortel-Van der Aa综合征,这是神经发育障碍.
ADNP对胚胎发育至关重要,但其调节作用尚不清楚.
需要阐明ADNP在转录调节中的功能及其对细胞命运决定的影响.

研究的目的:

研究ADNP在转录调节和细胞命运决定中的分子机制.
描述由ADNP,CHD4和HP1形成的蛋白质复合体.
了解ADNP突变如何导致Helsmoortel-Van der Aa综合征.

主要方法:

形成和表征ADNP-CHD4-HP1复合体 (ChAHP).
在Euchromatin中对DNA基因的CHAHP结合的分析.
在小鼠胚胎干细胞中对ChAHP成分进行基因切除.
与HP1介导的沉默相比,对ChAHP介导的抑制机制的研究.

主要成果:

ADNP与CHD4和HP1形成一个稳定的复合体,ChAHP.
ChAHP与欧克罗马丁中的特定DNA基因结合.
ChAHP介导的抑制局部受限,与HP1介导的沉默不同.
导致自发分化和神经元发育受损.
在ADNP中无意义的突变破坏了CHAHP的完整性,符合Helsmoortel-Van der Aa综合征.

结论:

通过ChAHP复合体,ADNP调节细胞命运决定的基因表达.
在细胞命运可塑性中ChAHP的作用可能解释ADNP突变的多器官效应.
针对早期停止密码体的核糖体读取的治疗策略可能对患者有益.

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