{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T12:44:16Z","timestamp":1782909856301,"version":"3.54.5"},"posted":{"date-parts":[[2025,3,27]]},"group-title":"Microbiology","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T00:00:00Z","timestamp":1743033600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health, National Institute of Allergy and Infectious Disease","award":["1R01AI153396"],"award-info":[{"award-number":["1R01AI153396"]}]},{"name":"Anonymous donor","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Herpes simplex virus 1 (HSV-1) is a highly prevalent DNA virus with a major impact on human health. The HSV-1 genome is assembled into silenced stable chromatin and minimally transcribed during latency or assembled into permissive highly dynamic chromatin and highly transcribed during lytic infections. It is unclear how HSV-1 genomes transition between chromatin states, but epigenetics, including chromatin dynamics, have been proposed to play a major role. Chromatin remodeling complexes regulate cellular chromatin dynamics and contribute to DNA transcription, replication, and repair. The BAF family of chromatin remodeling complexes includes three ubiquitously expressed complexes (cBAF, PBAF, and GBAF) and several cell type-specific ones. Some common BAF subunits interact with two HSV-1 proteins, VP16 or ICP8.<\/jats:p>\n                <jats:p>Three subunits shared by all BAF complexes and a unique subunit from each cBAF, PBAF, and GBAF were enriched in herpes nuclear domains (HND), the novel nuclear domains formed during lytic infection in which HSV-1 genomes are transcribed, replicated, and packaged. The shared ATPase SMARCA4 bound, directly or indirectly, to HSV-1 genomes. Bromodomains bind to acetylated histones and may thus be involved in this binding. However, none of four structurally unrelated inhibitors of BAF bromodomains drastically affected the recruitment of BAF subunits to HND, and neither of four commonly acetylated histone residues recognized by BAF bromodomains was enriched in the HND. BAF complexes are thus recruited to the HND by their interactions with VP16, which activates viral transcription, and ICP8. Surprisingly, the BAF complexes recruited by VP16 and ICP8 participate in inhibition of immediate-early, early, and early-late HSV-1 transcription, but not DNA replication or late transcription. We propose that BAF complexes are recruited to the HND by VP16 and ICP8, independently of their bromodomains, to inhibit viral transcription early in infection, thus contributing to the regulated cascade of gene expression. These findings also have implications to epigenetic anticancer drugs, in that it should be considered whether their use may reactivate latent herpes simplex viruses.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Author Summary<\/jats:title>\n                  <jats:p>Herpes simplex virus 1 (HSV-1) infects over two-thirds of the world population. HSV-1 establishes latency in neurons, resulting in life-long infection. Although most infections are asymptomatic, reactivation can produce a wide range of clinical manifestations, including cold sores, stromal keratitis, and encephalitis. Available treatments do not prevent reactivation or eliminate latent viral reservoirs, as no viral proteins are expressed during latency. Epigenetic regulation plays a role during the lytic and latent cycles. Lytic HSV-1 chromatin is highly dynamic whereas latent chromatin is stable. Chromatin dynamics are regulated by multiple factors, including the chromatin remodeling complexes. Here we show that the BAF chromatin remodeling complexes regulate HSV-1 transcription during lytic infection in primary fibroblast and transformed epithelial human cells. Although these complexes are recruited to the viral genomes by viral proteins, they counterintuitively downregulate viral transcription before the onset of DNA replication. We propose that BAF complexes play a major role in the regulation of the orchestrated cascade of viral gene expression and propose to consider the potential for reactivation of herpes simplex viruses when using epigenetic inhibitors in the treatment of cancer.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.03.27.645673","type":"posted-content","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T04:30:26Z","timestamp":1743136226000},"source":"Crossref","is-referenced-by-count":0,"title":["BAF chromatin remodeling complexes inhibit immediate-early and early, but not late, transcription of herpes simplex virus 1"],"prefix":"10.64898","author":[{"given":"Sarah M","family":"Saddoris","sequence":"first","affiliation":[{"name":"Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University, Ithaca, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5789-8590","authenticated-orcid":false,"given":"Luis M","family":"Schang","sequence":"additional","affiliation":[{"name":"Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University, Ithaca, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026070103351057000_2025.03.27.645673v2.1","doi-asserted-by":"publisher","DOI":"10.2471\/BLT.19.237149"},{"key":"2026070103351057000_2025.03.27.645673v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.aivir.2015.10.001"},{"key":"2026070103351057000_2025.03.27.645673v2.3","doi-asserted-by":"crossref","unstructured":"Singh N , Tscharke DC . 2020. Herpes Simplex Virus Latency Is Noisier the Closer We Look. J Virol 94.","DOI":"10.1128\/JVI.01701-19"},{"key":"2026070103351057000_2025.03.27.645673v2.4","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01934-09"},{"key":"2026070103351057000_2025.03.27.645673v2.5","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01468-12"},{"key":"2026070103351057000_2025.03.27.645673v2.6","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.02015-23:e0201523"},{"key":"2026070103351057000_2025.03.27.645673v2.7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008076"},{"key":"2026070103351057000_2025.03.27.645673v2.8","doi-asserted-by":"crossref","first-page":"105103","DOI":"10.1016\/j.antiviral.2021.105103","article-title":"Chromatin-mediated epigenetic regulation of HSV-1 transcription as a potential target in antiviral therapy","volume":"192","year":"2021","journal-title":"Antiviral Research"},{"key":"2026070103351057000_2025.03.27.645673v2.9","doi-asserted-by":"publisher","DOI":"10.1080\/14787210.2024.2420329"},{"issue":"265r","key":"2026070103351057000_2025.03.27.645673v2.10","first-page":"a169","article-title":"Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes","volume":"6","year":"2014","journal-title":"Sci Transl Med"},{"issue":"167r","key":"2026070103351057000_2025.03.27.645673v2.11","first-page":"a5","article-title":"Targeting the JMJD2 histone demethylases to epigenetically control herpesvirus infection and reactivation from latency","volume":"5","year":"2013","journal-title":"Sci Transl Med"},{"key":"2026070103351057000_2025.03.27.645673v2.12","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00712-09"},{"key":"2026070103351057000_2025.03.27.645673v2.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2015.11.007"},{"key":"2026070103351057000_2025.03.27.645673v2.14","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00633-16"},{"key":"2026070103351057000_2025.03.27.645673v2.15","first-page":"e00415","article-title":"The CCCTC Binding Factor, CTRL2, Modulates Heterochromatin Deposition and the Establishment of Herpes Simplex Virus 1 Latency In Vivo","volume":"93","year":"2019","journal-title":"Journal of Virology"},{"key":"2026070103351057000_2025.03.27.645673v2.16","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.26"},{"key":"2026070103351057000_2025.03.27.645673v2.17","doi-asserted-by":"publisher","DOI":"10.1038\/366170a0"},{"key":"2026070103351057000_2025.03.27.645673v2.18","doi-asserted-by":"crossref","unstructured":"Bayona-Feliu A , Barroso S , Mu\u00f1oz S , Aguilera A . 2021. The SWI\/SNF chromatin remodeling complex helps resolve R-loop-mediated transcription\u2013replication conflicts. Nature Genetics.","DOI":"10.1038\/s41588-021-00867-2"},{"key":"2026070103351057000_2025.03.27.645673v2.19","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.pharmthera.2018.05.001","article-title":"ARID1A loss in cancer: Towards a mechanistic understanding","volume":"190","year":"2018","journal-title":"Pharmacology & Therapeutics"},{"key":"2026070103351057000_2025.03.27.645673v2.20","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a026450"},{"key":"2026070103351057000_2025.03.27.645673v2.21","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.3390\/cancers11121859","article-title":"The Emerging Roles of ATP-Dependent Chromatin Remodeling Complexes in Pancreatic Cancer","volume":"11","year":"2019","journal-title":"Cancers"},{"key":"2026070103351057000_2025.03.27.645673v2.22","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2219"},{"key":"2026070103351057000_2025.03.27.645673v2.23","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3389\/fnmol.2017.00243","article-title":"Chromatin Remodeling BAF (SWI\/SNF) Complexes in Neural Development and Disorders","volume":"10","year":"2017","journal-title":"Frontiers in Molecular Neuroscience"},{"key":"2026070103351057000_2025.03.27.645673v2.24","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.145.7.1341"},{"key":"2026070103351057000_2025.03.27.645673v2.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(03)00048-4"},{"key":"2026070103351057000_2025.03.27.645673v2.26","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02349-08"},{"key":"2026070103351057000_2025.03.27.645673v2.27","unstructured":"Kobiler O , Weitzman MD . Herpes simplex virus replication compartments: From naked release to recombining together. PLoS Pathogens."},{"key":"2026070103351057000_2025.03.27.645673v2.28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004939"},{"key":"2026070103351057000_2025.03.27.645673v2.29","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.11.5856-5866.2004"},{"key":"2026070103351057000_2025.03.27.645673v2.30","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00330&ndash;10"},{"key":"2026070103351057000_2025.03.27.645673v2.31","doi-asserted-by":"crossref","unstructured":"Ho PJ , Lloyd SM , Bao X . 2019. Unwinding chromatin at the right places: how BAF is targeted to specific genomic locations during development. Development.","DOI":"10.1242\/dev.178780"},{"key":"2026070103351057000_2025.03.27.645673v2.32","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1007\/s00438-022-01863-9","article-title":"The SWI\/SNF subunit BRG1 affects alternative splicing by changing RNA binding factor interactions with nascent RNA","volume":"297","year":"2022","journal-title":"Molecular genetics and genomics: MGG"},{"key":"2026070103351057000_2025.03.27.645673v2.33","doi-asserted-by":"crossref","unstructured":"Dykhuizen EC , Hargreaves DC , Miller EL , Cui K , Korshunov A , Kool M , Pfister S , Cho Y-J , Zhao K , Crabtree GR . 2013. BAF complexes facilitate decatenation of DNA by topoisomerase II\u03b1. Nature.","DOI":"10.1038\/nature12146"},{"key":"2026070103351057000_2025.03.27.645673v2.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2023.103609"},{"key":"2026070103351057000_2025.03.27.645673v2.35","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1038\/s41467-020-16443-x","article-title":"The bromodomain containing protein BRD-9 orchestrates RAD51\u2013RAD54 complex formation and regulates homologous recombination-mediated repair","volume":"11","year":"2020","journal-title":"Nature Communications"},{"key":"2026070103351057000_2025.03.27.645673v2.36","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad609"},{"key":"2026070103351057000_2025.03.27.645673v2.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.04.013"},{"key":"2026070103351057000_2025.03.27.645673v2.38","doi-asserted-by":"publisher","DOI":"10.1042\/BST20190960"},{"key":"2026070103351057000_2025.03.27.645673v2.39","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80315-9"},{"key":"2026070103351057000_2025.03.27.645673v2.40","doi-asserted-by":"crossref","first-page":"5551","DOI":"10.1038\/s41467-020-19402-8","article-title":"Functional characterization of SMARCA4 variants identified by targeted exome-sequencing of 131,668 cancer patients","volume":"11","year":"2020","journal-title":"Nature Communications"},{"key":"2026070103351057000_2025.03.27.645673v2.41","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.Cd-21-1491"},{"key":"2026070103351057000_2025.03.27.645673v2.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2022.03.027"},{"key":"2026070103351057000_2025.03.27.645673v2.43","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1186\/s12943-022-01643-4","article-title":"Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program","volume":"21","year":"2022","journal-title":"Molecular Cancer"},{"key":"2026070103351057000_2025.03.27.645673v2.44","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201501394"},{"key":"2026070103351057000_2025.03.27.645673v2.45","doi-asserted-by":"publisher","DOI":"10.1021\/ACS.JMEDCHEM.5B00256\/SUPPL_FILE\/JM5B00256_SI_001.PDF"},{"key":"2026070103351057000_2025.03.27.645673v2.46","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b01865"},{"key":"2026070103351057000_2025.03.27.645673v2.47","doi-asserted-by":"crossref","first-page":"100874","DOI":"10.1016\/j.jlr.2025.100874","article-title":"Chromatin remodeler BRD9 represses transcription of PPAR\u03b1 target genes, including CPT1A to suppress lipid metabolism","volume":"66","year":"2025","journal-title":"Journal of Lipid Research"},{"key":"2026070103351057000_2025.03.27.645673v2.48","doi-asserted-by":"crossref","first-page":"5800","DOI":"10.1038\/s41467-019-13608-1","article-title":"PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth","volume":"10","year":"2019","journal-title":"Nature Communications"},{"key":"2026070103351057000_2025.03.27.645673v2.49","doi-asserted-by":"crossref","first-page":"e970072","DOI":"10.4161\/23723548.2014.970072","article-title":"The PBAF chromatin remodeling complex represses transcription and promotes rapid repair at DNA double-strand breaks","volume":"2","year":"2015","journal-title":"Mol Cell Oncol"},{"key":"2026070103351057000_2025.03.27.645673v2.50","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01723-14"},{"key":"2026070103351057000_2025.03.27.645673v2.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2004.10.002"},{"key":"2026070103351057000_2025.03.27.645673v2.52","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.18.9689-9696.2004"},{"key":"2026070103351057000_2025.03.27.645673v2.53","doi-asserted-by":"crossref","unstructured":"Field NR , Dickson K-A , Nassif NT , Marsh DJ . 2024. SMARCA4 and SMARCA2 co-deficiency: An uncommon molecular signature defining a subset of rare, aggressive, and undifferentiated malignancies associated with defective chromatin remodeling. Cancer Letters 605.","DOI":"10.1016\/j.canlet.2024.217282"},{"key":"2026070103351057000_2025.03.27.645673v2.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.013"},{"key":"2026070103351057000_2025.03.27.645673v2.55","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s13073-021-00871-5","article-title":"PRMT1-mediated H4R3me2a recruits SMARCA4 to promote colorectal cancer progression by enhancing EGFR signaling","volume":"13","year":"2021","journal-title":"Genome Medicine"},{"key":"2026070103351057000_2025.03.27.645673v2.56","unstructured":"Anonymous. IL24 - The Human Protein Atlas. Accessed"},{"key":"2026070103351057000_2025.03.27.645673v2.57","unstructured":"Anonymous. GAPDH - The Human Protein Atlas. Accessed"},{"key":"2026070103351057000_2025.03.27.645673v2.58","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1500723"},{"key":"2026070103351057000_2025.03.27.645673v2.59","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M117.067116"},{"key":"2026070103351057000_2025.03.27.645673v2.60","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006721"},{"key":"2026070103351057000_2025.03.27.645673v2.61","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/18.9.2449"},{"key":"2026070103351057000_2025.03.27.645673v2.62","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-20-0289"},{"key":"2026070103351057000_2025.03.27.645673v2.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2020.104730"},{"key":"2026070103351057000_2025.03.27.645673v2.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2009.08.004"},{"key":"2026070103351057000_2025.03.27.645673v2.65","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.18.10178-10186.2004"},{"key":"2026070103351057000_2025.03.27.645673v2.66","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01575-08"},{"key":"2026070103351057000_2025.03.27.645673v2.67","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01727-09"},{"key":"2026070103351057000_2025.03.27.645673v2.68","doi-asserted-by":"crossref","first-page":"9614","DOI":"10.1038\/s41467-024-53981-0","article-title":"The BAF complex enhances transcription through interaction with H3K56ac in the histone globular domain","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2026070103351057000_2025.03.27.645673v2.69","doi-asserted-by":"crossref","first-page":"9614","DOI":"10.1038\/s41467-024-53981-0","article-title":"The BAF complex enhances transcription through interaction with H3K56ac in the histone globular domain","volume":"15","year":"2024","journal-title":"Nature Communications"},{"key":"2026070103351057000_2025.03.27.645673v2.70","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf8705"},{"key":"2026070103351057000_2025.03.27.645673v2.71","doi-asserted-by":"publisher","DOI":"10.2217\/fvl.15.18"},{"key":"2026070103351057000_2025.03.27.645673v2.72","doi-asserted-by":"crossref","unstructured":"Mertens ME , Knipe DM . 2021. Herpes Simplex Virus 1 Manipulates Host Cell Antiviral and Proviral DNA Damage Responses. mBio 12:10.1128\/mbio.03552-20.","DOI":"10.1128\/mBio.03552-20"},{"key":"2026070103351057000_2025.03.27.645673v2.73","doi-asserted-by":"crossref","unstructured":"Birkenheuer C , Dunn L , Dufour R , Baines J . March 2022 2022. ICP22 of Herpes Simplex Virus 1 Decreases RNA Polymerase Processivity. Accessed","DOI":"10.1128\/jvi.02191-21"},{"key":"2026070103351057000_2025.03.27.645673v2.74","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00219-09"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.03.27.645673","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T11:49:04Z","timestamp":1782906544000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.03.27.645673"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,27]]},"references-count":74,"URL":"https:\/\/doi.org\/10.1101\/2025.03.27.645673","relation":{},"subject":[],"published":{"date-parts":[[2025,3,27]]},"subtype":"preprint"}}