{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T08:06:42Z","timestamp":1779782802179,"version":"3.53.1"},"reference-count":58,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":6,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2024-05181"],"award-info":[{"award-number":["RGPIN-2024-05181"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000082","name":"Cystic Fibrosis Canada","doi-asserted-by":"publisher","award":["1011927"],"award-info":[{"award-number":["1011927"]}],"id":[{"id":"10.13039\/501100000082","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Inorganic polyphosphate (polyP) is a highly conserved linear polymer of orthophosphate, present across nearly all living organisms. Its functional diversity, particularly through recently discovered post-translational modifications, has garnered increasing scientific interest. However, its role in gene regulation, especially in mammalian systems, remains unexplored. In this study, we present findings that demonstrate that polyP multi-targets the super-enhancer complex to regulate gene expression, marking a novel mechanism of transcriptional control. We show that polyP modifies key components of the complex, including the Mediator subunit MED1, the coactivator Bromodomain-containing protein 4 (BRD4), and the transcriptional regulator Yin Yang 1 (YY1). This polyP-mediated modification not only disrupts their ability to undergo phase separation but also downregulates the expression of MED1 and BRD4, as well as impairs the nuclear localization of YY1. Furthermore, polyP inhibits YY1 dimer formation and disrupts YY1-mediated DNA looping, leading to suppressed gene expression. These discoveries highlight polyP as a novel regulator of super-enhancer-driven gene transcription and provide new insights into the broader role of polyP in epigenetic regulation. This work uncovers a previously unknown layer of gene control, positioning polyP as a critical player in transcriptional regulation through its interaction with transcription factors and coactivators.<\/jats:p>","DOI":"10.1093\/nar\/gkag530","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T12:03:36Z","timestamp":1778760216000},"source":"Crossref","is-referenced-by-count":0,"title":["Polyphosphate as a novel regulator of super-enhancer complexes: disruption of phase separation and gene expression"],"prefix":"10.1093","volume":"54","author":[{"given":"Zhiyun","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Biomedical and Molecular Sciences, Queen\u2019s University , Kingston, ON K7L 3N6 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9322-9394","authenticated-orcid":false,"given":"Zongchao","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences, Queen\u2019s University , Kingston, ON K7L 3N6 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"2026052603504336800_B1","doi-asserted-by":"publisher","first-page":"11734","DOI":"10.1016\/S0021-9258(19)38459-5","article-title":"Polyphosphate kinase from Escherichia coli. Purification and demonstration of a phosphoenzyme intermediate","volume":"265","author":"Ahn","year":"1990","journal-title":"J Biol Chem"},{"key":"2026052603504336800_B2","doi-asserted-by":"publisher","first-page":"16684","DOI":"10.1073\/pnas.262655299","article-title":"Polyphosphate kinase (PPK2), a potent, polyphosphate-driven generator of GTP","volume":"99","author":"Ishige","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026052603504336800_B3","doi-asserted-by":"publisher","first-page":"16678","DOI":"10.1073\/pnas.262655199","article-title":"A polyphosphate kinase (PPK2) widely conserved in bacteria","volume":"99","author":"Zhang","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026052603504336800_B4","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/S0021-9258(18)54198-3","article-title":"An exopolyphosphatase of Escherichia coli. The enzyme and its ppx gene in a polyphosphate operon","volume":"268","author":"Akiyama","year":"1993","journal-title":"J Biol Chem"},{"key":"2026052603504336800_B5","doi-asserted-by":"publisher","first-page":"9636","DOI":"10.1073\/pnas.170283397","article-title":"Polyphosphate kinase is essential for biofilm development, quorum sensing, and virulence of Pseudomonas aeruginosa","volume":"97","author":"Rashid","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026052603504336800_B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nmicrobiol.2016.267","article-title":"The anti-inflammatory drug mesalamine targets bacterial polyphosphate accumulation","volume":"2","author":"Dahl","year":"2017","journal-title":"Nat Microbiol"},{"key":"2026052603504336800_B7","doi-asserted-by":"publisher","first-page":"e0059221","DOI":"10.1128\/mBio.00592-21","article-title":"A dual-specificity inhibitor targets polyphosphate kinase 1 and 2 enzymes to attenuate virulence of Pseudomonas aeruginosa","volume":"12","author":"Neville","year":"2021","journal-title":"mBio"},{"key":"2026052603504336800_B8","doi-asserted-by":"publisher","first-page":"4309","DOI":"10.1091\/mbc.11.12.4309","article-title":"New components of a system for phosphate accumulation and polyphosphate metabolism in Saccharomyces cerevisiae revealed by genomic expression analysis","volume":"11","author":"Ogawa","year":"2000","journal-title":"MBoC"},{"key":"2026052603504336800_B9","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1126\/science.1168120","article-title":"Catalytic core of a membrane-associated eukaryotic polyphosphate polymerase","volume":"324","author":"Hothorn","year":"2009","journal-title":"Science"},{"key":"2026052603504336800_B10","doi-asserted-by":"publisher","first-page":"4035","DOI":"10.1038\/s41467-020-17639-x","article-title":"Bacterial polyphosphates interfere with the innate host defense to infection","volume":"11","author":"Roewe","year":"2020","journal-title":"Nat Commun"},{"key":"2026052603504336800_B11","doi-asserted-by":"publisher","first-page":"5972","DOI":"10.1182\/blood-2012-03-306605","article-title":"Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation","volume":"119","author":"Morrissey","year":"2012","journal-title":"Blood"},{"key":"2026052603504336800_B12","doi-asserted-by":"publisher","first-page":"44250","DOI":"10.1074\/jbc.M406261200","article-title":"Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes","volume":"279","author":"Ruiz","year":"2004","journal-title":"J Biol Chem"},{"key":"2026052603504336800_B13","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.cell.2009.11.001","article-title":"Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo","volume":"139","author":"M\u00fcller","year":"2009","journal-title":"Cell"},{"key":"2026052603504336800_B14","doi-asserted-by":"publisher","first-page":"9707","DOI":"10.1021\/bi8010847","article-title":"Human metastasis regulator protein H-prune is a short-chain exopolyphosphatase","volume":"47","author":"Tammenkoski","year":"2008","journal-title":"Biochemistry"},{"key":"2026052603504336800_B15","doi-asserted-by":"publisher","first-page":"31966","DOI":"10.1074\/jbc.M111.266320","article-title":"Identification of an evolutionarily conserved family of inorganic polyphosphate endopolyphosphatases","volume":"286","author":"Lonetti","year":"2011","journal-title":"J Biol Chem"},{"key":"2026052603504336800_B16","doi-asserted-by":"crossref","first-page":"110004","DOI":"10.1016\/j.celrep.2021.110004","article-title":"Polyphosphate degradation by Nudt3-Zn2+ mediates oxidative stress response","volume":"37","author":"Samper-Mart\u00edn","year":"2021","journal-title":"Cell Rep"},{"key":"2026052603504336800_B17","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.molcel.2015.02.010","article-title":"Protein polyphosphorylation of lysine residues by inorganic polyphosphate","volume":"58","author":"Azevedo","year":"2015","journal-title":"Mol Cell"},{"key":"2026052603504336800_B18","doi-asserted-by":"publisher","first-page":"3427","DOI":"10.1016\/j.celrep.2018.02.104","article-title":"A screen for candidate targets of lysine polyphosphorylation uncovers a conserved network implicated in ribosome biogenesis","volume":"22","author":"Bentley-DeSousa","year":"2018","journal-title":"Cell Rep"},{"key":"2026052603504336800_B19","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1002\/1873-3468.13588","article-title":"Proteins required for vacuolar function are targets of lysine polyphosphorylation in yeast","volume":"594","author":"McCarthy","year":"2020","journal-title":"FEBS Lett"},{"key":"2026052603504336800_B20","doi-asserted-by":"publisher","first-page":"1958","DOI":"10.1021\/acschembio.8b00357","article-title":"Screening a protein array with synthetic biotinylated inorganic polyphosphate to define the human polyP-ome","volume":"13","author":"Azevedo","year":"2018","journal-title":"ACS Chem. Biol."},{"key":"2026052603504336800_B21","doi-asserted-by":"crossref","first-page":"113082","DOI":"10.1016\/j.celrep.2023.113082","article-title":"Modification of histidine repeat proteins by inorganic polyphosphate","volume":"42","author":"Neville","year":"2023","journal-title":"Cell Rep"},{"key":"2026052603504336800_B22","doi-asserted-by":"publisher","first-page":"11249","DOI":"10.1073\/pnas.1534805100","article-title":"Inorganic polyphosphate stimulates mammalian TOR, a kinase involved in the proliferation of mammary cancer cells","volume":"100","author":"Wang","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026052603504336800_B23","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1111\/jth.12899","article-title":"Inorganic polyphosphate elicits pro-inflammatory responses through activation of the mammalian target of rapamycin complexes 1 and 2 in vascular endothelial cells","volume":"13","author":"Hassanian","year":"2015","journal-title":"J Thromb Haemost"},{"key":"2026052603504336800_B24","doi-asserted-by":"crossref","first-page":"108318","DOI":"10.1016\/j.celrep.2020.108318","article-title":"A broad response to intracellular long-chain polyphosphate in human cells","volume":"33","author":"Bondy-Chorney","year":"2020","journal-title":"Cell Rep"},{"key":"2026052603504336800_B25","doi-asserted-by":"publisher","first-page":"18091","DOI":"10.1073\/pnas.0708959104","article-title":"Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death","volume":"104","author":"Abramov","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026052603504336800_B26","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.dnarep.2017.08.001","article-title":"Polyphosphate is a key factor for cell survival after DNA damage in eukaryotic cells","volume":"57","author":"Bru","year":"2017","journal-title":"DNA Repair"},{"key":"2026052603504336800_B27","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.1016\/j.molcel.2024.03.028","article-title":"Polyphosphate attachment to lysine repeats is a non-covalent protein modification","volume":"84","author":"Neville","year":"2024","journal-title":"Mol Cell"},{"key":"2026052603504336800_B28","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.cell.2013.03.035","article-title":"Master transcription factors and mediator establish super-enhancers at key cell identity genes","volume":"153","author":"Whyte","year":"2013","journal-title":"Cell"},{"key":"2026052603504336800_B29","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1016\/j.cell.2013.09.053","article-title":"Super-enhancers in the control of cell identity and disease","volume":"155","author":"Hnisz","year":"2013","journal-title":"Cell"},{"key":"2026052603504336800_B30","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.cell.2013.03.036","article-title":"Selective inhibition of tumor oncogenes by disruption of super-enhancers","volume":"153","author":"Lov\u00e9n","year":"2013","journal-title":"Cell"},{"key":"2026052603504336800_B31","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/j.cell.2016.12.013","article-title":"Transcriptional addiction in cancer","volume":"168","author":"Bradner","year":"2017","journal-title":"Cell"},{"key":"2026052603504336800_B32","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.pharmthera.2019.02.014","article-title":"Super-enhancers in cancer","volume":"199","author":"Thandapani","year":"2019","journal-title":"Pharmacol Ther"},{"key":"2026052603504336800_B33","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/ng.3167","article-title":"What are super-enhancers?","volume":"47","author":"Pott","year":"2015","journal-title":"Nat Genet"},{"key":"2026052603504336800_B34","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1016\/j.ccr.2013.11.003","article-title":"Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma","volume":"24","author":"Chapuy","year":"2013","journal-title":"Cancer Cell"},{"key":"2026052603504336800_B35","doi-asserted-by":"publisher","first-page":"eaar3958","DOI":"10.1126\/science.aar3958","article-title":"Coactivator condensation at super-enhancers links phase separation and gene control","volume":"361","author":"Sabari","year":"2018","journal-title":"Science"},{"key":"2026052603504336800_B36","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1016\/j.cell.2018.10.042","article-title":"Transcription factors activate genes through the phase-separation capacity of their activation domains","volume":"175","author":"Boija","year":"2018","journal-title":"Cell"},{"key":"2026052603504336800_B37","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1126\/science.aar4199","article-title":"Mediator and RNA polymerase II clusters associate in transcription-dependent condensates","volume":"361","author":"Cho","year":"2018","journal-title":"Science"},{"key":"2026052603504336800_B38","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1016\/S1357-2725(97)00085-X","article-title":"Transcription factors: an overview","volume":"29","author":"Latchman","year":"1997","journal-title":"Int J Biochem Cell Biol"},{"key":"2026052603504336800_B39","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1016\/j.cell.2018.01.029","article-title":"The human transcription factors","volume":"172","author":"Lambert","year":"2018","journal-title":"Cell"},{"key":"2026052603504336800_B40","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1038\/sj.onc.1209080","article-title":"Transcription factor YY1: structure, function, and therapeutic implications in cancer biology","volume":"25","author":"Gordon","year":"2006","journal-title":"Oncogene"},{"key":"2026052603504336800_B41","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.ygeno.2008.09.013","article-title":"YY1\u2019s longer DNA-binding motifs","volume":"93","author":"Do\u00a0Kim","year":"2009","journal-title":"Genomics"},{"key":"2026052603504336800_B42","doi-asserted-by":"publisher","first-page":"e1000397","DOI":"10.1371\/journal.pgen.1000397","article-title":"Genome-wide analysis of histidine repeats reveals their role in the localization of human proteins to the nuclear speckles compartment","volume":"5","author":"Salichs","year":"2009","journal-title":"PLoS Genet"},{"key":"2026052603504336800_B43","doi-asserted-by":"publisher","first-page":"4917","DOI":"10.1093\/nar\/gkac233","article-title":"A histidine cluster determines YY1-compartmentalized coactivators and chromatin elements in phase-separated enhancer clusters","volume":"50","author":"Wang","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"2026052603504336800_B44","doi-asserted-by":"publisher","first-page":"1573","DOI":"10.1016\/j.cell.2017.11.008","article-title":"YY1 is a structural regulator of enhancer-promoter loops","volume":"171","author":"Weintraub","year":"2017","journal-title":"Cell"},{"key":"2026052603504336800_B45","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1038\/nrg3296","article-title":"DNA secondary structures: stability and function of G-quadruplex structures","volume":"13","author":"Bochman","year":"2012","journal-title":"Nat Rev Genet"},{"key":"2026052603504336800_B46","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/s41589-020-00695-1","article-title":"YY1 interacts with guanine quadruplexes to regulate DNA looping and gene expression","volume":"17","author":"Li","year":"2021","journal-title":"Nat Chem Biol"},{"key":"2026052603504336800_B47","doi-asserted-by":"publisher","first-page":"3461","DOI":"10.1002\/elps.200700041","article-title":"Sensitive fluorescence detection of polyphosphate in polyacrylamide gels using 4\u2032, 6-diamidino-2-phenylindol","volume":"28","author":"Smith","year":"2007","journal-title":"Electrophoresis"},{"key":"2026052603504336800_B48","doi-asserted-by":"publisher","first-page":"a040683","DOI":"10.1101\/cshperspect.a040683","article-title":"Liquid\u2013liquid phase separation in chromatin","volume":"14","author":"Rippe","year":"2022","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2026052603504336800_B49","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1016\/j.jmb.2006.04.031","article-title":"The structure of the exopolyphosphatase (PPX) from Escherichia coli O157: H7 suggests a binding mode for long polyphosphate chains","volume":"359","author":"Rangarajan","year":"2006","journal-title":"J Mol Biol"},{"key":"2026052603504336800_B50","doi-asserted-by":"publisher","first-page":"3161","DOI":"10.1128\/AEM.02705-08","article-title":"Exopolyphosphatases PPX1 and PPX2 from corynebacterium glutamicum","volume":"75","author":"Lindner","year":"2009","journal-title":"Appl Environ Microb"},{"key":"2026052603504336800_B51","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.trechm.2019.07.002","article-title":"The structure and function of DNA G-quadruplexes","volume":"2","author":"Spiegel","year":"2020","journal-title":"Trends Chem"},{"key":"2026052603504336800_B52","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1111\/j.1471-4159.1971.tb00222.x","article-title":"Evidence for the occurrence and distribution of inorganic polyphosphates in vertebrate tissues","volume":"18","author":"Gabel","year":"1971","journal-title":"J Neurochem"},{"key":"2026052603504336800_B53","doi-asserted-by":"publisher","first-page":"5818","DOI":"10.1074\/jbc.270.11.5818","article-title":"Inorganic polyphosphate in mammalian cells and tissues (\u2217)","volume":"270","author":"Kumble","year":"1995","journal-title":"J Biol Chem"},{"key":"2026052603504336800_B54","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/j.tibs.2024.06.010","article-title":"Back on the chain gang: polyphosphate modification of proteins","volume":"49","author":"Neville","year":"2024","journal-title":"Trends Biochem Sci"},{"key":"2026052603504336800_B55","doi-asserted-by":"publisher","first-page":"e5021","DOI":"10.1002\/pro.5021","article-title":"Protein purification via consecutive histidine\u2013polyphosphate interaction","volume":"33","author":"Zhou","year":"2024","journal-title":"Protein Sci"},{"key":"2026052603504336800_B56","doi-asserted-by":"publisher","first-page":"910","DOI":"10.15252\/embr.201540607","article-title":"G4-associated human diseases","volume":"16","author":"Maizels","year":"2015","journal-title":"EMBO Rep"},{"key":"2026052603504336800_B57","doi-asserted-by":"publisher","first-page":"6673","DOI":"10.1093\/nar\/gkab500","article-title":"G-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells","volume":"49","author":"Miglietta","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"2026052603504336800_B58","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/j.tim.2021.02.002","article-title":"Inorganic polyphosphate in host and microbe biology","volume":"29","author":"Bowlin","year":"2021","journal-title":"Trends Microbiol"}],"container-title":["Nucleic Acids Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/54\/10\/gkag530\/68391125\/gkag530.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/54\/10\/gkag530\/68391125\/gkag530.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T07:50:50Z","timestamp":1779781850000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nar\/article\/doi\/10.1093\/nar\/gkag530\/8693977"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,20]]},"references-count":58,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,5,20]]}},"URL":"https:\/\/doi.org\/10.1093\/nar\/gkag530","relation":{},"ISSN":["0305-1048","1362-4962"],"issn-type":[{"value":"0305-1048","type":"print"},{"value":"1362-4962","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,6,10]]},"published":{"date-parts":[[2026,5,20]]},"article-number":"gkag530"}}