{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T02:08:51Z","timestamp":1789697331406,"version":"4.0.1"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2021,8,8]],"date-time":"2021-08-08T00:00:00Z","timestamp":1628380800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2018YFA0507300"],"award-info":[{"award-number":["2018YFA0507300"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81630063"],"award-info":[{"award-number":["81630063"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81971959"],"award-info":[{"award-number":["81971959"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31771419"],"award-info":[{"award-number":["31771419"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31721003"],"award-info":[{"award-number":["31721003"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81971967"],"award-info":[{"award-number":["81971967"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2020YFC1200105"],"award-info":[{"award-number":["2020YFC1200105"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jiangsu Provincial Project of Invigorating Health Care through Science, Technology and Education"},{"name":"Jiangsu Provincial Commission of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Gametocytogenesis, the process by which malaria parasites produce sexual forms that can infect mosquitoes, is essential for the transmission of malaria. A transcriptional switch of the pfap2-g gene triggers sexual commitment, but how the complex multi-step process is precisely programed remains largely unknown. Here, by systematic functional screening of a panel of ApiAP2 transcription factors, we identify six new ApiAP2 members associated with gametocytogenesis in Plasmodium falciparum. Among these, PfAP2-G5 (PF3D7_1139300) was found to be indispensable for gametocytogenesis. This factor suppresses the transcriptional activity of the pfap2-g gene via binding to both the upstream region and exonic gene body, the latter is linked to the maintenance of local heterochromatin structure, thereby preventing initiation of sexual commitment. Removal of this repressive effect through pfap2-g5 knockout disrupts the asexual replication cycle and promotes sexual commitment accompanied by upregulation of pfap2-g expression. However, the gametocytes produced fail to mature fully. Further analyses show that PfAP2-G5 is essential for gametocyte maturation, and causes the down-regulation of pfap2-g and a set of early gametocyte genes activated by PfAP2-G prior to gametocyte development. Collectively, our findings reveal a regulation cascade of gametocyte production in malaria parasites, and provide a new target for transmission blocking interventions.<\/jats:p>","DOI":"10.1093\/nar\/gkab683","type":"journal-article","created":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T07:13:08Z","timestamp":1627456388000},"page":"9264-9279","source":"Crossref","is-referenced-by-count":76,"title":["A cascade of transcriptional repression determines sexual commitment and development in\n                    <i>Plasmodium falciparum<\/i>"],"prefix":"10.1093","volume":"49","author":[{"given":"Xiaomin","family":"Shang","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Parasitology, Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education of China,\u00a0East Hospital, School of Medicine, Tongji University, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2641-889X","authenticated-orcid":false,"given":"Shijun","family":"Shen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, the School of Life Sciences and Technology, Tongji University, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxia","family":"Tang","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi 214064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqin","family":"He","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi 214064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuemeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Parasitology, Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education of China,\u00a0East Hospital, School of Medicine, Tongji University, Shanghai 200120, China"},{"name":"Unit of Human Parasite Molecular and Cell Biology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5406-2360","authenticated-orcid":false,"given":"Changhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Parasitology, Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education of China,\u00a0East Hospital, School of Medicine, Tongji University, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"He","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Parasitology, Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education of China,\u00a0East Hospital, School of Medicine, Tongji University, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gangqiang","family":"Guo","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Parasitology, Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education of China,\u00a0East Hospital, School of Medicine, Tongji University, Shanghai 200120, China"},{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, the School of Life Sciences and Technology, Tongji University, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, the School of Life Sciences and Technology, Tongji University, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, the School of Life Sciences and Technology, Tongji University, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianshu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, the School of Life Sciences and Technology, Tongji University, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, the School of Life Sciences and Technology, Tongji University, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cizhong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, the School of Life Sciences and Technology, Tongji University, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meihua","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi 214064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Yu","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi 214064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiping","family":"Han","sequence":"additional","affiliation":[{"name":"Unit of Human Parasite Molecular and Cell Biology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Culleton","sequence":"additional","affiliation":[{"name":"Division of Molecular Parasitology, Proteo-Science Centre, Ehime University, Matsuyama, Ehime 790-8577, Japan"},{"name":"Department of Protozoology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Unit of Human Parasite Molecular and Cell Biology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5298-9234","authenticated-orcid":false,"given":"Jun","family":"Cao","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi 214064, China"},{"name":"Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Public Health Research Center, Jiangnan University, Wuxi 214122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Gu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, the School of Life Sciences and Technology, Tongji University, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8759-9102","authenticated-orcid":false,"given":"Qingfeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Parasitology, Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education of China,\u00a0East Hospital, School of Medicine, Tongji University, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,8,7]]},"reference":[{"key":"2021092000040215800_B1","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/nrmicro3519","article-title":"Sexual development in Plasmodium parasites: knowing when it's time to commit","volume":"13","author":"Josling","year":"2015","journal-title":"Nat. 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Microbiol."},{"key":"2021092000040215800_B3","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nature12920","article-title":"A transcriptional switch underlies commitment to sexual development in malaria parasites","volume":"507","author":"Kafsack","year":"2014","journal-title":"Nature"},{"key":"2021092000040215800_B4","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nature12970","article-title":"A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium","volume":"507","author":"Sinha","year":"2014","journal-title":"Nature"},{"key":"2021092000040215800_B5","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/nature24280","article-title":"Single-cell RNA sequencing reveals a signature of sexual commitment in malaria parasites","volume":"551","author":"Poran","year":"2017","journal-title":"Nature"},{"key":"2021092000040215800_B6","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1038\/s41564-018-0223-6","article-title":"Inducible developmental reprogramming redefines commitment to sexual development in the malaria parasite Plasmodium berghei","volume":"3","author":"Kent","year":"2018","journal-title":"Nat. Microbiol."},{"key":"2021092000040215800_B7","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/s41564-018-0291-7","article-title":"Revisiting the initial steps of sexual development in the malaria parasite Plasmodium falciparum","volume":"4","author":"Bancells","year":"2019","journal-title":"Nat. Microbiol."},{"key":"2021092000040215800_B8","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1186\/s12864-019-6322-9","article-title":"Hierarchical transcriptional control regulates Plasmodium falciparum sexual differentiation","volume":"20","author":"van\u00a0Biljon","year":"2019","journal-title":"BMC Genomics"},{"key":"2021092000040215800_B9","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1038\/s41467-020-15026-0","article-title":"Dissecting the role of PfAP2-G in malaria gametocytogenesis","volume":"11","author":"Josling","year":"2020","journal-title":"Nat. Commun."},{"key":"2021092000040215800_B10","doi-asserted-by":"crossref","first-page":"eaaz5057","DOI":"10.1126\/sciadv.aaz5057","article-title":"Conditional expression of PfAP2-G for controlled massive sexual conversion in","volume":"6","author":"Llor\u00e0-Batlle","year":"2020","journal-title":"Sci. Adv."},{"key":"2021092000040215800_B11","doi-asserted-by":"crossref","first-page":"12824","DOI":"10.1073\/pnas.1504389112","article-title":"Global transcriptional repression: An initial and essential step for Plasmodium sexual development","volume":"112","author":"Yuda","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021092000040215800_B12","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.chom.2016.12.003","article-title":"A knockout screen of ApiAP2 genes reveals networks of interacting transcriptional regulators controlling the Plasmodium life cycle","volume":"21","author":"Modrzynska","year":"2017","journal-title":"Cell Host Microbe."},{"key":"2021092000040215800_B13","doi-asserted-by":"crossref","first-page":"e01986-17","DOI":"10.1128\/mBio.01986-17","article-title":"Systematic CRISPR\u2013Cas9-mediated modifications of Plasmodium yoelii ApiAP2 genes reveal functional insights into parasite development","volume":"8","author":"Zhang","year":"2017","journal-title":"mBio"},{"key":"2021092000040215800_B14","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.chom.2014.07.004","article-title":"Heterochromatin protein 1 secures survival and transmission of malaria parasites","volume":"16","author":"Brancucci","year":"2014","journal-title":"Cell Host Microbe"},{"key":"2021092000040215800_B15","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.chom.2014.06.014","article-title":"A Plasmodium falciparum histone deacetylase regulates antigenic variation and gametocyte conversion","volume":"16","author":"Coleman","year":"2014","journal-title":"Cell Host Microbe"},{"key":"2021092000040215800_B16","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1126\/science.aan6042","article-title":"GDV1 induces sexual commitment of malaria parasites by antagonizing HP1-dependent gene silencing","volume":"359","author":"Filarsky","year":"2018","journal-title":"Science"},{"key":"2021092000040215800_B17","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1038\/s41467-019-10172-6","article-title":"Plasmodium falciparum sexual differentiation in malaria patients is associated with host factors and GDV1-dependent genes","volume":"10","author":"Usui","year":"2019","journal-title":"Nat. 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Microbiol."},{"key":"2021092000040215800_B23","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.chom.2017.05.006","article-title":"Red blood cell Invasion by the malaria parasite is coordinated by the PfAP2-I transcription factor","volume":"21","author":"Santos","year":"2017","journal-title":"Cell Host Microbe"},{"key":"2021092000040215800_B24","doi-asserted-by":"crossref","first-page":"14042","DOI":"10.1038\/s41598-017-12578-y","article-title":"An ApiAP2 member regulates expression of clonally variant genes of the human malaria parasite Plasmodium falciparum","volume":"7","author":"Martins","year":"2017","journal-title":"Sci. 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