{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:44:23Z","timestamp":1778219063800,"version":"3.51.4"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,12,21]],"date-time":"2020-12-21T00:00:00Z","timestamp":1608508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["11871070"],"award-info":[{"award-number":["11871070"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["2020B1515020047"],"award-info":[{"award-number":["2020B1515020047"]}]},{"name":"Central Universities","award":["20ykzd20"],"award-info":[{"award-number":["20ykzd20"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,22]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Inferring how gene expression in a cell is influenced by cellular microenvironment is of great importance yet challenging. In this study, we present a single-cell RNA-sequencing data based multilayer network method (scMLnet) that models not only functional intercellular communications but also intracellular gene regulatory networks (https:\/\/github.com\/SunXQlab\/scMLnet). scMLnet was applied to a scRNA-seq dataset of COVID-19 patients to decipher the microenvironmental regulation of expression of SARS-CoV-2 receptor ACE2 that has been reported to be correlated with inflammatory cytokines and COVID-19 severity. The predicted elevation of ACE2 by extracellular cytokines EGF, IFN-\u03b3 or TNF-\u03b1 were experimentally validated in human lung cells and the related signaling pathway were verified to be significantly activated during SARS-COV-2 infection. Our study provided a new approach to uncover inter-\/intra-cellular signaling mechanisms of gene expression and revealed microenvironmental regulators of ACE2 expression, which may facilitate designing anti-cytokine therapies or targeted therapies for controlling COVID-19 infection. In addition, we summarized and compared different methods of scRNA-seq based inter-\/intra-cellular signaling network inference for facilitating new methodology development and applications.<\/jats:p>","DOI":"10.1093\/bib\/bbaa327","type":"journal-article","created":{"date-parts":[[2020,10,26]],"date-time":"2020-10-26T12:08:28Z","timestamp":1603714108000},"page":"988-1005","source":"Crossref","is-referenced-by-count":117,"title":["Inferring microenvironmental regulation of gene expression from single-cell RNA sequencing data using scMLnet with an application to COVID-19"],"prefix":"10.1093","volume":"22","author":[{"given":"Jinyu","family":"Cheng","sequence":"first","affiliation":[{"name":"Zhong-Shan School of Medicine, Sun Yat-Sen University"}]},{"given":"Ji","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer 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