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Despite viral genomes being smaller and more gene dense than their hosts, we generally lack a sense of scope for the features governing the transcriptional output of individual viral genes. Even having a seemingly simple expression pattern does not imply that a gene\u2019s underlying regulation is straightforward. Here, we illustrate this by combining high-density functional genomics, expression profiling, and viral-specific chromosome conformation capture to define with unprecedented detail the transcriptional regulation of a single gene from Kaposi\u2019s sarcoma-associated herpesvirus (KSHV). We used as our model KSHV ORF68 \u2013 which has simple, early expression kinetics and is essential for viral genome packaging. We first identified seven cis-regulatory regions involved in ORF68 expression by densely tiling the ~154\u2009kb KSHV genome with dCas9 fused to a transcriptional repressor domain (CRISPRi). A parallel Cas9 nuclease screen indicated that three of these regions act as promoters of genes that regulate ORF68. RNA expression profiling demonstrated that three more of these regions act by either repressing or enhancing other distal viral genes involved in ORF68 transcriptional regulation. Finally, we tracked how the 3D structure of the viral genome changes during its lifecycle, revealing that these enhancing regulatory elements are physically closer to their targets when active, and that disrupting some elements caused large-scale changes to the 3D genome. These data enable us to construct a complete model revealing that the mechanistic diversity of this essential regulatory circuit matches that of human genes.<\/jats:p>","DOI":"10.1038\/s44320-024-00075-0","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T04:29:31Z","timestamp":1731990571000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Enhancers and genome conformation provide complex transcriptional control of a herpesviral gene"],"prefix":"10.1038","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5005-0669","authenticated-orcid":false,"given":"David W","family":"Morgens","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4667-8867","authenticated-orcid":false,"given":"Leah","family":"Gulyas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowen","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0037-4822","authenticated-orcid":false,"given":"Alejandro","family":"Rivera-Madera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabelle S","family":"Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0479-9377","authenticated-orcid":false,"given":"Britt A","family":"Glaunsinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,19]]},"reference":[{"key":"75_CR1","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nature12787","volume":"507","author":"R Andersson","year":"2014","unstructured":"Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, Chen Y, Zhao X, Schmidl C, Suzuki T et al (2014) An atlas of active enhancers across human cell types and tissues. 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