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Controlling gene expression with deep generative design of regulatory DNA

Design of de novo synthetic regulatory DNA is a promising avenue to control gene expression in biotechnology and medicine. Using mutagenesis typically requires screening sizable random DNA libraries, which limits the designs to span merely a short section of the promoter and restricts their control...

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Detalles Bibliográficos
Autores principales: Zrimec, Jan, Fu, Xiaozhi, Muhammad, Azam Sheikh, Skrekas, Christos, Jauniskis, Vykintas, Speicher, Nora K., Börlin, Christoph S., Verendel, Vilhelm, Chehreghani, Morteza Haghir, Dubhashi, Devdatt, Siewers, Verena, David, Florian, Nielsen, Jens, Zelezniak, Aleksej
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9427793/
https://www.ncbi.nlm.nih.gov/pubmed/36042233
http://dx.doi.org/10.1038/s41467-022-32818-8
Descripción
Sumario:Design of de novo synthetic regulatory DNA is a promising avenue to control gene expression in biotechnology and medicine. Using mutagenesis typically requires screening sizable random DNA libraries, which limits the designs to span merely a short section of the promoter and restricts their control of gene expression. Here, we prototype a deep learning strategy based on generative adversarial networks (GAN) by learning directly from genomic and transcriptomic data. Our ExpressionGAN can traverse the entire regulatory sequence-expression landscape in a gene-specific manner, generating regulatory DNA with prespecified target mRNA levels spanning the whole gene regulatory structure including coding and adjacent non-coding regions. Despite high sequence divergence from natural DNA, in vivo measurements show that 57% of the highly-expressed synthetic sequences surpass the expression levels of highly-expressed natural controls. This demonstrates the applicability and relevance of deep generative design to expand our knowledge and control of gene expression regulation in any desired organism, condition or tissue.