使用自回归语言模型设计现实的调节DNA
Avantika Lal1, David Garfield2, Tommaso Biancalani3
1Biology Research|AI Development, gRED Computational Sciences, Genentech, South San Francisco, California 94080, USA; lal.avantika@gene.com eraslan.gokcen@gene.com.
Genome research
|September 25, 2024
概括
研究人员开发了regLM,该框架使用语言模型来设计合成基因调控元素,如促进剂和增强剂. 这种工具可以创建具有生物制造和疗法的特定活动的DNA序列.
科学领域:
- 基因组学和分子生物学
- 合成生物学 合成生物学
- 生物信息学是一种生物信息学.
背景情况:
- 控制基因表达的Cis-regulatory元素 (CREs),包括促进剂和增强剂,通过特定的DNA序列控制基因表达.
- CRE活动取决于转录因子 (TF) 结合基因的排列,组成和间距.
- 越来越需要合成CREs,以适合生物制造和先进疗法 (如细胞和基因疗法) 的应用.
研究的目的:
- 引入 regLM,这是一种用于设计具有可预测和所需功能性质的合成CREs的新型计算框架.
- 为了能够创建具有特定活动水平 (高,低) 或细胞类型特定表达模式的CREs.
- 为CRE设计利用自回归语言模型和监督序列到函数模型.
主要方法:
- 开发了regLM框架,将自回归语言模型与监督的序列到函数模型集成在一起.
- 利用regLM来设计具有细胞类型特定活性的合成酵母促进剂和人体增强剂.
- 采用计算模型来预测设计合成CREs的功能和生物相关性.
主要成果:
- 通过使用 regLM 框架成功设计了具有针对性的活性配置文件的合成酵母促进剂和人体增强剂.
- 证明了计算设计的CREs预计会显示出所需的功能.
- 表明合成CREs具有与实验验证天然CREs相比较的生物特征.
结论:
- regLM提供了一种有效的计算方法,用于设计具有特定功能特征的合成 cis-regulatory 元素.
- 该框架有助于为各种生物技术和治疗应用创建现实的调节性DNA序列.
- regLM 提供了对复杂的控制基因表达的 cis 调节代码的宝贵见解.
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