追踪基因表达和染色体结构的共同基础
bioRxiv : the preprint server for biology
|April 16, 2025
概括
拓关联域 (TADs) 积极调节基因,影响细胞发育和疾病中的可塑性. 新的方法揭示了TADs.
科学领域:
- 基因组学和分子生物学
- 计算生物学 计算生物学
- 基因法规 基因法规
背景情况:
- 染色体的三维组织成拓关联域 (TADs) 通过调解长距离基因相互作用,影响基因调节.
- 定义TAD边界和评估它们对基因表达的直接影响的技术局限性阻碍了对TAD功能的充分理解.
研究的目的:
- 开发新的方法来定义TAD及其基因组成,使新的功能解释和捕捉特定物种的组织差异.
- 为了利用一个生成的人工智能基础模型来实现上下文相似性,以更好地代表功能性基因关系,而不是传统的共同表达方法.
- 研究TADs在基因共同调节,细胞可塑性,发育,衰老和疾病中的作用,并开发癌症药物反应的预测工具.
主要方法:
- 开发了人类和老鼠的共识TAD地图,使用"基因袋"方法.
- 利用在3300万个转录组上训练的生成性AI基础模型来定义上下文相似性.
- 创建了"TAD签名",用于对单细胞转录组数据进行增强的统计分析.
主要成果:
- 证明TADs积极促进基因共同调节,可能通过转录凝聚物.
- 发现TAD介导的转录增强在早期发育期间最强,随着年龄的增长而减弱.
- 在化疗改变的癌细胞中观察到不同的TAD使用模式,表明细胞可塑性中的作用.
- 开发了"TAD签名"以从转录基因数据中改善对癌症细胞系药物反应的预测.
结论:
- 通过TADs的染色体组织在基因协调和细胞可塑性中发挥着积极的作用.
- 在不同发育阶段,衰老和癌症等疾病状态中,TAD的功能和影响各不相同.
- TADs通过概率机制运作,为了解和治疗疾病提供新的途径.
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