美国哈佛医学院Luca Pinello课题组的最新研究揭示了使用生成式AI框架DNA扩散设计合成调控元件。相关论文于2025年12月23日发表在《自然—遗传学》杂志上。

在这里，研究人员介绍了DNA-Diffusion，这是一个生成式人工智能框架，主题机器学习训练来自不同细胞系的DNA可及性数据，以设计具有细胞类型特异性活性的紧凑调节元件。课题组发现DNA-Diffthemion产生200个碱基对的合成元件，这些元件概括了内源性转录因子结合语法，同时表现出增强的细胞类型特异性。小组验证了这些元素，并在三个细胞系中对5850个元素的STARR-seq库进行了主题化。

此外，课题组成功地展示了内源性基因调节EXTRA-seq主题，在其原生基因组背景下重新激活AXIN2，一个白血病保护基因。他们的方法优于现有的计算方法，在保持序列多样性的同时平衡功能活性和细胞类型特异性。这项工作建立了DNA-Diffthemion作为一个强大的工具，用于工程紧凑，高度特异性的调控元件，对推进基因治疗和理解基因调控至关重要。

据了解，系统地设计精确的基因表达控制调控元件仍然是基因组学和合成生物学的核心挑战。

附：英文原文

Title: Designing synthetic regulatory elements using the generative AI framework DNA-Diffusion

Author: DaSilva, Lucas Ferreira, Senan, Simon, Kribelbauer-Swietek, Judith F., Patel, Zain Munir, Louis, Lithin Karmel, Reddy, Aniketh Janardhan, Gabbita, Sameer, Rosen, Jonathan D., Nussbaum, Zach, Crdova, Csar Miguel Valdez, Wenteler, Aaron, Weber, Noah, Tunjic, Tin M., Mansoldo, Martino, Khan, Talha Ahmad, Hwang, Gue-Ho, Gardeux, Vincent, Humphreys, David T., Smith, Cameron, Bejan, Matei, Bromley, Peter, Connell, Will, Deplancke, Bart, Love, Michael I., Wong, Emily S., Meuleman, Wouter, Pinello, Luca

Issue&Volume: 2025-12-23

Abstract: Systematically designing regulatory elements for precise gene expression control remains a central challenge in genomics and synthetic biology. Here we introduce DNA-Diffusion, a generative artificial intelligence framework that uses machine learning trained on DNA accessibility data from diverse cell lines to design compact regulatory elements with cell-type-specific activity. We show that DNA-Diffusion generates 200-base-pair synthetic elements that recapitulate endogenous transcription factor binding grammar while exhibiting enhanced cell-type specificity. We validated these elements using a 5,850-element STARR-seq library across three cell lines. Moreover, we demonstrated successful endogenous gene modulation using EXTRA-seq, reactivating AXIN2, a leukemia-protective gene, in its native genomic context. Our approach outperforms existing computational methods in balancing functional activity with cell-type specificity while maintaining sequence diversity. This work establishes DNA-Diffusion as a powerful tool for engineering compact, highly specific regulatory elements crucial for advancing gene therapies and understanding gene regulation.

DOI: 10.1038/s41588-025-02441-6

Source: https://www.nature.com/articles/s41588-025-02441-6