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Here, we introduce an algorithm, eNet, to build enhancer networks by integrating single-cell chromatin accessibility and gene expression profiles. The complexity of enhancer networks is assessed by two metrics: the number of enhancers and the frequency of predicted enhancer interactions (PEIs) based on chromatin co-accessibility. We apply eNet\u00a0algorithm to a human blood dataset and find cell identity and disease genes tend to be regulated by complex enhancer networks. The network hub enhancers (enhancers with frequent PEIs) are the most functionally important. Compared with super-enhancers, enhancer networks show better performance in predicting cell identity and disease genes. eNet is robust and widely applicable in various human or mouse tissues datasets. Thus, we propose a model of enhancer networks containing three modes: Simple, Multiple and Complex, which are distinguished by their complexity in regulating gene expression. Taken together, our work provides an unsupervised approach to simultaneously identify key cell identity and disease genes and explore the underlying regulatory relationships among enhancers in single cells.<\/jats:p>","DOI":"10.1093\/bib\/bbac508","type":"journal-article","created":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T12:57:13Z","timestamp":1666702633000},"source":"Crossref","is-referenced-by-count":11,"title":["Complexity of enhancer networks predicts cell identity and disease genes revealed by single-cell multi-omics analysis"],"prefix":"10.1093","volume":"24","author":[{"given":"Danni","family":"Hong","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen, Fujian 361102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongli","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen, Fujian 361102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lifang","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen, Fujian 361102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muya","family":"Shu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences , Beijing 100101, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianwu","family":"Dai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences , Beijing 100101, China"},{"name":"University of Chinese Academy of Sciences , Beijing 100049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8321-4818","authenticated-orcid":false,"given":"Falong","family":"Lu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences , Beijing 100101, China"},{"name":"University of Chinese Academy of Sciences , Beijing 100049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengsha","family":"Tong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen, Fujian 361102, China"},{"name":"National Institute for Data Science in Health and Medicine, Xiamen University , Xiamen, Fujian 361102, 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