Nested epistasis enhancer networks for robust genome regulation.

Journal: Science (New York, N.Y.)
PMID: 35951677

Abstract

Mammalian genomes have multiple enhancers spanning an ultralong distance (>megabases) to modulate important genes, but it is unclear how these enhancers coordinate to achieve this task. We combine multiplexed CRISPRi screening with machine learning to define quantitative enhancer-enhancer interactions. We find that the ultralong distance enhancer network has a nested multilayer architecture that confers functional robustness of gene expression. Experimental characterization reveals that enhancer epistasis is maintained by three-dimensional chromosomal interactions and BRD4 condensation. Machine learning prediction of synergistic enhancers provides an effective strategy to identify noncoding variant pairs associated with pathogenic genes in diseases beyond genome-wide association studies analysis. Our work unveils nested epistasis enhancer networks, which can better explain enhancer functions within cells and in diseases.

Authors

  • Xueqiu Lin
    Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • Yanxia Liu
    Key Laboratory of Big Data and Intelligent Robot (South China University of Technology), Ministry of Education,; School of Software Engineering, South China University of Technology, Guangzhou, China. Electronic address: cslyx@scut.edu.cn.
  • Shuai Liu
    Graduate School of Chinese Academy of Traditional Chinese Medicine, Beijing, China.
  • Xiang ZHU
  • Lingling Wu
    Department of Gastric Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.
  • Yanyu Zhu
    Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • Dehua Zhao
    Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • Xiaoshu Xu
    Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • Augustine Chemparathy
    School of Medicine, Stanford University, Stanford, CA 94305, USA.
  • Haifeng Wang
    Collaborative Innovation Center of Seafood Deep Processing, Institute of Seafood, Zhejiang Gongshang University, Hangzhou, 310012, China.
  • Yaqiang Cao
    Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung and Blood Institute NIH, Bethesda, MD 20892, USA.
  • Muneaki Nakamura
    Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • Jasprina N Noordermeer
    Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • Marie La Russa
    Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • Wing Hung Wong
    Department of Statistics, Stanford University, Stanford, CA 94305, USA.
  • Keji Zhao
    Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung and Blood Institute NIH, Bethesda, MD 20892, USA.
  • Lei S Qi
    Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.

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