通过LLPS介导的转录程序,ARID3B的遗传调节赋予了带有/没有裂口口腔的裂口敏感性
Xiaofeng Li1, Dandan Li1, Shu Lou1
1Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases (Nanjing Medical University), Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine (Nanjing Medical University), Nanjing, China.
研究人员确定ARID3B是非综合征裂唇与/或没有裂 palates (nsCL/P) 的关键遗传风险因素. 破坏了ARID3B的功能
科学领域:
- 遗传学 是一个遗传学.
- 发展生物学 发展生物学
- 分子生物学分子生物学
背景情况:
- 全基因组关联研究 (GWAS) 已经将许多遗传位点与非综合征裂唇与/或没有裂 palates (nsCL/P) 联系起来.
- 这些位点的nsCL/P背后的特定因果基因和分子机制需要系统地调查.
研究的目的:
- 系统地研究与nsCL/P.相关的候选基因和分子机制.
- 确定主要风险基因及其在nsCL/P发育中的功能作用.
主要方法:
- 采用多组学选策略来识别候选基因.
- 研究了一种特定变异 (rs1821848) 对基因调节和蛋白质相互作用的功能影响.
- 研究了液体-液体相分离 (LLPS) 在体外和体内涉及ARID3B的作用.
- 利用斑马鱼模型来评估ARID3B中断的表型后果.
主要成果:
- 确定了20个候选基因,其中ARID3B被确定为nsCL/P最重要的风险基因.
- 发现一种因果变体rs1821848降低了NR2C2结合,导致ARID3B上调.
- 通过LLPS,ARID3B通过LLPS形成颗粒,并招募SMAD2/3联合激活剂来启动nsCL/P相关的基因表达.
- 在斑马鱼模型中破坏ARID3B的LLPS挽救了细胞缺陷和表型异常.
结论:
- ARID3B是nsCL/P发育中的关键因果基因,通过依赖LLPS的机制起作用.
- 变种rs1821848影响ARID3B的表达及其在nsCL/P病变发生中的作用.
- 针对ARID3B介导的LLPS为nsCL/P提供了一个潜在的治疗途径.
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