A novel interpretable deep learning-based computational framework designed synthetic enhancers with broad cross-species activity.

Journal: Nucleic acids research
PMID: 39420601

Abstract

Enhancers play a critical role in dynamically regulating spatial-temporal gene expression and establishing cell identity, underscoring the significance of designing them with specific properties for applications in biosynthetic engineering and gene therapy. Despite numerous high-throughput methods facilitating genome-wide enhancer identification, deciphering the sequence determinants of their activity remains challenging. Here, we present the DREAM (DNA cis-Regulatory Elements with controllable Activity design platforM) framework, a novel deep learning-based approach for synthetic enhancer design. Proficient in uncovering subtle and intricate patterns within extensive enhancer screening data, DREAM achieves cutting-edge sequence-based enhancer activity prediction and highlights critical sequence features implicating strong enhancer activity. Leveraging DREAM, we have engineered enhancers that surpass the potency of the strongest enhancer within the Drosophila genome by approximately 3.6-fold. Remarkably, these synthetic enhancers exhibited conserved functionality across species that have diverged more than billion years, indicating that DREAM was able to learn highly conserved enhancer regulatory grammar. Additionally, we designed silencers and cell line-specific enhancers using DREAM, demonstrating its versatility. Overall, our study not only introduces an interpretable approach for enhancer design but also lays out a general framework applicable to the design of other types of cis-regulatory elements.

Authors

  • Zhaohong Li
    Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Buxin Road NO. 97, Dapeng District, Shenzhen 518124, China.
  • Yuanyuan Zhang
    National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China.
  • Bo Peng
    Institute for Environmental and Climate Research, Jinan University, Guangzhou, China.
  • Shenghua Qin
    Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Buxin Road NO. 97, Dapeng District, Shenzhen 518124, China.
  • Qian Zhang
    The Neonatal Intensive Care Unit, Peking Union Medical College Hospital, Peking, China.
  • Yun Chen
  • Choulin Chen
    Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Buxin Road NO. 97, Dapeng District, Shenzhen 518124, China.
  • Yongzhou Bao
    Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518124, China.
  • Yuqi Zhu
    Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, NO. 7 Pengfei Road, Dapeng District, Shenzhen 518124, China.
  • Yi Hong
    Department of Product Engineering, MedeAnalytics, Inc., Emeryville, CA, USA.
  • Binghua Liu
    State Key Laboratory of Maricultural Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, NO.106 Nanjing Road, Shinan District, Qingdao, Shandong 266071, China.
  • Qian Liu
    State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
  • Lingna Xu
    Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Buxin Road NO. 97, Dapeng District, Shenzhen 518124, China.
  • Xi Chen
    Department of Critical care medicine, Shenzhen Hospital, Southern Medical University, Guangdong, Shenzhen, China.
  • Xinhao Ma
    College of Grassland Agriculture, National Beef Cattle Improvement Center, College of Animal Science and Technology, Northwest A&F University, NO. 3 Taicheng Road, Yangling District, Yangling, Shaanxi 712100, China.
  • Hongyan Wang
    State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200432, China.
  • Long Xie
    Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104 (J.D.R., L.X., A.K., J.M.E., T.C., I.M.N., S.M., J.C.G.); Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, Calif (J.D.R., A.M.R.); Penn Image Computing and Science Laboratory, University of Pennsylvania, Philadelphia, Pa (X.L., J.W.); University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.T.D.); Mecklenburg Radiology Associates, Charlotte, NC (E.J.B.); Department of Radiology, University of Texas, Austin, Tex (R.N.B.); and Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, University of Pennsylvania, Philadelphia, Pa (I.M.N.).
  • Yilong Yao
    Green Healthy Aquaculture Research Center, Kunpeng Institute of Modern Agriculture at Foshan, Chinese Academy of Agricultural Sciences, Building 26 Lihe Technology Park, Auxiliary Road of Xinxi Avenue South, Nanhai District, Foshan 528226, China.
  • Biao Deng
    Department of Cardiothoracic Surgery, Affiliated Hospital of Guangdong Medical University, Xiashan District, Zhanjiang, Guangdong, China. 15760562638@163.com.
  • Jiaying Li
    Zhejiang Key Laboratory of Excited-State Energy Conversion and Energy Storage, Department of Chemistry, Zhejiang University, Hangzhou 310058, China.
  • Baojun De
    College of Life Sciences, Inner Mongolia Autonomous Region Key Laboratory of Biomanufacturing, Inner Mongolia Agricultural University, NO. 306 Zhaowuda Road, Saihan District, Hohhot 010018, China.
  • Yuting Chen
    Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.
  • Jing Wang
    Endoscopy Center, Peking University Cancer Hospital and Institute, Beijing, China.
  • Tian Li
    College of Plant Protection, Southwest University, Chongqing, China.
  • Ranran Liu
    Institute of Animal Science, Chinese Academy of Agricultural Sciences, Yuanmingyuan West Road NO. 2, Haidian District, Beijing 100193, China.
  • Zhonglin Tang
    Green Healthy Aquaculture Research Center, Kunpeng Institute of Modern Agriculture at Foshan, Chinese Academy of Agricultural Sciences, Building 26 Lihe Technology Park, Auxiliary Road of Xinxi Avenue South, Nanhai District, Foshan 528226, China.
  • Junwei Cao
    College of Life Sciences, Inner Mongolia Autonomous Region Key Laboratory of Biomanufacturing, Inner Mongolia Agricultural University, NO. 306 Zhaowuda Road, Saihan District, Hohhot 010018, China.
  • Erwei Zuo
    Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China. zuoerwei@caas.cn.
  • Chugang Mei
    College of Grassland Agriculture, National Beef Cattle Improvement Center, College of Animal Science and Technology, Northwest A&F University, NO. 3 Taicheng Road, Yangling District, Yangling, Shaanxi 712100, China.
  • Fangjie Zhu
    College of JUNCAO Science and Ecology, Haixia Institute of Science and Technology, National Engineering Research Center of JUNCAO, Fujian Agriculture and Forestry University (FAFU), NO.15 Shangxiadian Road, Cangshan District, Fuzhou 0350002, China.
  • Changwei Shao
    State Key Laboratory of Maricultural Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, NO.106 Nanjing Road, Shinan District, Qingdao, Shandong 266071, China.
  • Guirong Wang
    Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, 13210.
  • Tongjun Sun
    Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, NO. 7 Pengfei Road, Dapeng District, Shenzhen 518124, China.
  • Ningli Wang
  • Gang Liu
    Department of Interventional Radiology, Qinghai Red Cross Hospital, Xining, Qinghai, China.
  • Jian-Quan Ni
    Gene Regulatory Lab, School of Basic Medical Sciences, Tsinghua University, NO. 30 Shuangqing road, Haidian district, Beijing 100084, China.
  • Yuwen Liu
    Department of Orthopaedic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, China.

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