{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T10:01:33Z","timestamp":1769767293541,"version":"3.49.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T00:00:00Z","timestamp":1619481600000},"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\/501100012246","name":"Priority Academic Program Development of Jiangsu Higher Education Institutions","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012246","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jiangsu Provincial Association for Maternal and Child Health Studies Commissioned Research","award":["JSFY202005"],"award-info":[{"award-number":["JSFY202005"]}]},{"name":"Foundation of Jiangsu Population Association","award":["JSPA2019017"],"award-info":[{"award-number":["JSPA2019017"]}]},{"name":"Medical Innovation Project of Logistics Service","award":["18JS005"],"award-info":[{"award-number":["18JS005"]}]},{"name":"Key Research & Development Program of Jiangsu Province","award":["BE2018713"],"award-info":[{"award-number":["BE2018713"]}]},{"name":"Key Foundation of Wuhan Huoshenshan Hospital","award":["2020[18]"],"award-info":[{"award-number":["2020[18]"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Studies have demonstrated that both mortality and severe illness rates exist significant difference in different gender COVID-19 patients, but the reasons are still very mysterious to date. Here, we firstly find that the survival outcome of female patients is better to male patients through analyzing the 3044 COVID-19 cases. Secondly, we identify many important master regulators [e.g. STAT1\/STAT2 and zinc finger (ZNF) proteins], in particular female patients can express more ZNF proteins and stronger transcriptional activities than male patients in response to SARS-CoV-2 infection. Thirdly, we discover that ZNF protein activity is significantly negative correlation with the SARS-CoV-2 load of COVID-19 patients, and ZNF proteins as transcription factors can also activate their target genes to participate in anti-SARS-CoV-2 infection. Fourthly, we demonstrate that ZNF protein activity is positive correlation with the abundance of multiple immune cells of COVID-19 patients, implying that the highly ZNF protein activity might promote the abundance and the antiviral activity of multiple immune cells to effectively suppress SARS-CoV-2 infection. Taken together, our study proposes an underlying anti-SARS-COV-2 role of ZNF proteins, and differences in the amount and activity of ZNF proteins might be responsible for the distinct prognosis of different gender COVID-19 patients.<\/jats:p>","DOI":"10.1093\/bib\/bbab118","type":"journal-article","created":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T12:11:43Z","timestamp":1615983103000},"source":"Crossref","is-referenced-by-count":21,"title":["Analyzing master regulators and scRNA-seq of COVID-19 patients reveals an underlying anti-SARS-CoV-2 mechanism of ZNF proteins"],"prefix":"10.1093","volume":"22","author":[{"given":"Shijie","family":"Qin","sequence":"first","affiliation":[{"name":"Comparative Genomics and Bioinformatics Laboratory of the College of Life Sciences, Nanjing Normal University, China"}]},{"given":"Weijun","family":"Xu","sequence":"additional","affiliation":[{"name":"COVID-19 Research Center, Institute of laboratory medicine, Jinling Hospital, Nanjing University School of medicine, the first school of clinical medicine, Southern Medical University, China"}]},{"given":"Canbiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Comparative Genomics and Bioinformatics Laboratory of the College of Life Sciences, Nanjing Normal University, China"}]},{"given":"Sizhu","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Arts and Sciences, Emory University, Atlanta, USA"}]},{"given":"Wei","family":"Dai","sequence":"additional","affiliation":[{"name":"COVID-19 Research Center, Institute of laboratory medicine, Jinling Hospital, Nanjing University School of medicine, the first school of clinical medicine, Southern Medical University, China"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"COVID-19 Research Center, Institute of laboratory medicine, Jinling Hospital, Nanjing University School of medicine, the first school of clinical medicine, Southern Medical University, China"}]},{"given":"Jiawei","family":"Shen","sequence":"additional","affiliation":[{"name":"COVID-19 Research Center, Institute of laboratory medicine, Jinling Hospital, Nanjing University School of medicine, the first school of clinical medicine, Southern Medical University, China"}]},{"given":"Ping","family":"Jin","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Genomics and Bioinformatics, School of Life Sciences, Nanjing Normal University, China"}]},{"given":"Fei","family":"Ma","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Genomics and Bioinformatics at the School of Life Sciences, Nanjing Normal University, China"}]},{"given":"Xinyi","family":"Xia","sequence":"additional","affiliation":[{"name":"COVID-19 Research Center, Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine; Nanjing Clinical College of Southern Medical University, Nanjing, China"}]}],"member":"286","published-online":{"date-parts":[[2021,4,27]]},"reference":[{"key":"2021090815525465300_ref1","first-page":"2495","volume-title":"Clin Infect Dis.","author":"Yang","year":"2020"},{"key":"2021090815525465300_ref2","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1016\/j.mayocp.2020.05.014","article-title":"Sex Differences in Case Fatality Rate of COVID-19: Insights From a Multinational Registry","volume":"95","author":"Alkhouli","year":"2020","journal-title":"Mayo Clin Proc."},{"key":"2021090815525465300_ref3","first-page":"6317","article-title":"Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission","volume-title":"Nat Commun","author":"Peckham","year":"2020"},{"key":"2021090815525465300_ref4","doi-asserted-by":"crossref","first-page":"108409","DOI":"10.1016\/j.clim.2020.108409","article-title":"Individual risk management strategy and potential therapeutic options for the COVID-19 pandemic","volume":"215","author":"Gasmi","year":"2020","journal-title":"Clin Immunol."},{"key":"2021090815525465300_ref5","doi-asserted-by":"crossref","first-page":"3188","DOI":"10.1093\/cid\/ciaa920","article-title":"Distinct clinical characteristics and risk factors for mortality in female COVID-19 inpatients with Coronavirus Disease 2019 (COVID-19): a sex-stratified large-scale cohort study in Wuhan, China","volume":"71","author":"Chen","year":"2020","journal-title":"Clin Infect Dis."},{"key":"2021090815525465300_ref6","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.maturitas.2020.06.017","article-title":"Coronavirus disease 2019 and gender-related mortality in European countries: a meta-analysis","volume":"141","author":"P\u00e9rez-L\u00f3pez","year":"2020","journal-title":"Maturitas"},{"key":"2021090815525465300_ref7","first-page":"e105114","article-title":"SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells","volume-title":"EMBO J.","author":"Lukassen","year":"2020"},{"key":"2021090815525465300_ref8","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"2021090815525465300_ref9","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1093\/eurheartj\/ehaa373","article-title":"Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors","volume":"41","author":"Sama","year":"2020","journal-title":"Eur Heart J."},{"key":"2021090815525465300_ref10","doi-asserted-by":"crossref","first-page":"E562","DOI":"10.1152\/ajpendo.00295.2020","article-title":"Sex-derived attributes contributing to SARS-CoV-2 mortality","volume":"319","author":"Chanana","year":"2020","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2021090815525465300_ref11","article-title":"Sex differences in immune responses that underlie COVID-19 disease outcomes","volume-title":"Nature","author":"Takahashi"},{"key":"2021090815525465300_ref12","doi-asserted-by":"crossref","DOI":"10.1002\/jmv.26137","article-title":"Gendered effects on inflammation reaction and outcome of COVID-19 patients in Wuhan","author":"Qin","year":"2020","journal-title":"J Med Virol"},{"key":"2021090815525465300_ref13","article-title":"Mechanistic insights into SARS-CoV-2 epidemic via revealing the features of SARS-CoV-2 coding proteins and host responses upon its infection","volume-title":"Bioinformatics","author":"Qin"},{"key":"2021090815525465300_ref14","doi-asserted-by":"crossref","first-page":"e3000849","DOI":"10.1371\/journal.pbio.3000849","article-title":"In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age","volume":"18","author":"Lieberman","year":"2020","journal-title":"PLoS Biol"},{"key":"2021090815525465300_ref15","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.abd1554","article-title":"Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19","volume-title":"Sci Immunol","author":"Lee"},{"key":"2021090815525465300_ref16","doi-asserted-by":"crossref","DOI":"10.1038\/s41591-020-0901-9","article-title":"Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19","volume-title":"Nat Med","author":"Liao"},{"key":"2021090815525465300_ref17","article-title":"edgeR: a Bioconductor package for differential expression analysis of digital gene expression data","volume-title":"Bioinformatics","author":"Robinson"},{"key":"2021090815525465300_ref18","doi-asserted-by":"crossref","DOI":"10.1093\/bib\/bby067","article-title":"Interpretation of differential gene expression results of RNA-seq data: review and integration","volume-title":"Brief Bioinform","author":"McDermaid"},{"issue":"Suppl 1","key":"2021090815525465300_ref19","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1186\/1471-2105-7-S1-S7","article-title":"ARACNE: an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context","volume":"7","author":"Margolin","year":"2006","journal-title":"BMC Bioinformatics."},{"key":"2021090815525465300_ref20","doi-asserted-by":"crossref","DOI":"10.1038\/ng.3593","article-title":"Functional characterization of somatic mutations in cancer using network-based inference of protein activity","volume-title":"Nat Genet","author":"Alvarez"},{"key":"2021090815525465300_ref21","article-title":"Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal center B cells","volume-title":"Blood","author":"Basso"},{"key":"2021090815525465300_ref22","article-title":"The transcriptional network for mesenchymal transformation of brain tumours","volume-title":"Nature","author":"Carro"},{"key":"2021090815525465300_ref23","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS."},{"key":"2021090815525465300_ref24","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-Seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinformatics."},{"key":"2021090815525465300_ref25","article-title":"Comprehensive Integration of Single-Cell Data","author":"Stuart","journal-title":"Cell"},{"key":"2021090815525465300_ref26","doi-asserted-by":"crossref","DOI":"10.1038\/nbt.4314","article-title":"Dimensionality reduction for visualizing single-cell data using UMAP","volume-title":"Nat Biotechnol","author":"Becht"},{"key":"2021090815525465300_ref27","doi-asserted-by":"crossref","first-page":"1107\u20131118","DOI":"10.1038\/s41590-020-0762-x","article-title":"Single-cell landscape of immunological responses in patients with COVID-19","volume":"21","author":"Zhang","year":"2020","journal-title":"Nat Immunol."},{"key":"2021090815525465300_ref28","doi-asserted-by":"crossref","first-page":"11555","DOI":"10.1128\/JVI.77.21.11555-11562.2003","article-title":"Expression of the zinc-finger antiviral protein inhibits alphavirus replication","volume":"77","author":"Bick","year":"2003","journal-title":"J Virol."},{"key":"2021090815525465300_ref29","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1126\/science.1074276","article-title":"Inhibition of retroviral RNA production by ZAP, a CCCH-type zinc finger protein","volume":"297","author":"Gao","year":"2002","journal-title":"Science"},{"key":"2021090815525465300_ref30","doi-asserted-by":"crossref","first-page":"e105114","DOI":"10.15252\/embj.2020105114","article-title":"SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells","volume":"39","author":"Lukassen","year":"2020","journal-title":"EMBO J."},{"key":"2021090815525465300_ref31","article-title":"SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor","volume-title":"Cell.","author":"Hoffmann"},{"key":"2021090815525465300_ref32","doi-asserted-by":"crossref","DOI":"10.1016\/j.molcel.2020.04.022","article-title":"Multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells","volume-title":"Mol Cell.","author":"Hoffmann"},{"key":"2021090815525465300_ref33","article-title":"Neuropilin-1 is a host factor for SARS-CoV-2 infection","volume-title":"Science.","author":"Daly"},{"key":"2021090815525465300_ref34","article-title":"Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity","volume-title":"Science.","author":"Cantuti-Castelvetri"},{"key":"2021090815525465300_ref35","doi-asserted-by":"crossref","DOI":"10.3390\/cancers12082325","article-title":"Sex hormones and hormone therapy during COVID-19 pandemic: implications for patients with cancer","volume-title":"Cancers (Basel)","author":"Cattrini"},{"key":"2021090815525465300_ref36","doi-asserted-by":"crossref","DOI":"10.1093\/femsre\/fuaa059","article-title":"Zinc finger proteins in the host-virus interplay: multifaceted functions based on their nucleic acid-binding property","volume-title":"FEMS Microbiol Rev","author":"Wang"},{"key":"2021090815525465300_ref37","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.01930-20","article-title":"SARS-CoV-2 is restricted by zinc finger antiviral protein despite preadaptation to the low-CpG environment in humans","volume-title":"mBio.","author":"Nchioua"},{"key":"2021090815525465300_ref38","doi-asserted-by":"crossref","DOI":"10.1038\/s41556-019-0416-0","article-title":"Mitochondria-localised ZNFX1 functions as a dsRNA sensor to initiate antiviral responses through MAVS","volume-title":"Nat Cell Biol","author":"Wang"},{"key":"2021090815525465300_ref39","article-title":"PLZF outreach: a finger in interferon's pie","volume-title":"Immunity","author":"Ozato"},{"key":"2021090815525465300_ref40","doi-asserted-by":"crossref","DOI":"10.1038\/nbt.3128","article-title":"C2H2 zinc finger proteins greatly expand the human regulatory lexicon","volume-title":"Nat Biotechnol","author":"Najafabadi"},{"key":"2021090815525465300_ref41","article-title":"Promyelocytic leukemia zinc finger protein regulates interferon-mediated innate immunity","volume-title":"Immunity","author":"Xu"},{"key":"2021090815525465300_ref42","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/JLB.1AB1119-314RRR","article-title":"CCCH-type zinc finger antiviral protein mediates antiviral immune response by activating T cells","volume":"107","author":"Zhu","year":"2020","journal-title":"J Leukoc Biol."},{"key":"2021090815525465300_ref43","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1402739111","article-title":"Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively spliced Igh product made by mature B lymphocytes","volume-title":"Proc Natl Acad Sci USA","author":"Enders"},{"key":"2021090815525465300_ref44","article-title":"Multiple genes encoding zinc finger domains are expressed in human T cells","volume-title":"New Biol","author":"Thiesen"},{"key":"2021090815525465300_ref45","doi-asserted-by":"crossref","DOI":"10.1101\/gr.4842106","article-title":"A comprehensive catalog of human KRAB-associated zinc finger genes: insights into the evolutionary history of a large family of transcriptional repressors","volume-title":"Genome Res","author":"Huntley"},{"key":"2021090815525465300_ref46","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1038\/s41556-019-0416-0","article-title":"Mitochondria-localised ZNFX1 functions as a dsRNA sensor to initiate antiviral responses through MAVS","volume":"21","author":"Wang","year":"2019","journal-title":"Nat Cell Biol."},{"key":"2021090815525465300_ref47","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00001-19","article-title":"ZAP, a CCCH-type zinc finger protein, inhibits porcine reproductive and respiratory syndrome virus replication and interacts with viral Nsp9","volume-title":"J Virol","author":"Zhao"},{"key":"2021090815525465300_ref48","first-page":"e02903","volume-title":"CpG frequency in the 5' third of the env gene determines sensitivity of primary HIV-1 strains to the Zinc-Finger antiviral protein","author":"Kmiec"},{"key":"2021090815525465300_ref49","doi-asserted-by":"crossref","DOI":"10.1002\/JLB.1AB1119-314RRR","article-title":"CCCH-type zinc finger antiviral protein mediates antiviral immune response by activating T cells","volume-title":"J Leukoc Biol","author":"Zhu"},{"key":"2021090815525465300_ref50","doi-asserted-by":"crossref","DOI":"10.1139\/bcb-2013-0096","article-title":"Chicken biliary exosomes enhance CD4(+)T proliferation and inhibit ALV-J replication in liver","volume-title":"Biochem Cell Biol","author":"Wang"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bib\/article-pdf\/22\/5\/bbab118\/40261829\/bbab118.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/bib\/article-pdf\/22\/5\/bbab118\/40261829\/bbab118.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T19:31:57Z","timestamp":1671651117000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbab118\/6255371"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,27]]},"references-count":50,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,9,2]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbab118","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"value":"1467-5463","type":"print"},{"value":"1477-4054","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,9]]},"published":{"date-parts":[[2021,4,27]]},"article-number":"bbab118"}}