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Here, we show that HCMV infection leads to widespread changes in human chromatin accessibility and chromatin looping, with hundreds of thousands of genomic regions affected 48 hr after infection. Integrative analyses reveal HCMV-induced perturbation of Hippo signaling through drastic reduction of TEAD1 transcription factor activity. We confirm extensive concordant loss of TEAD1 binding, active H3K27ac histone marks, and chromatin looping interactions upon infection. Our data position TEAD1 at the top of a hierarchy involving multiple altered important developmental pathways. HCMV infection reduces TEAD1 activity through four distinct mechanisms: closing of TEAD1-bound chromatin, reduction of YAP1 and phosphorylated YAP1 levels, reduction of TEAD1 transcript and protein levels, and alteration of\n                    <jats:italic>TEAD1<\/jats:italic>\n                    exon 6 usage. Altered TEAD1-based mechanisms are highly enriched at genetic risk loci associated with eye and ear development, providing mechanistic insight into HCMV\u2019s established roles in these processes.\n                  <\/jats:p>","DOI":"10.7554\/elife.101578","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T11:25:17Z","timestamp":1732706717000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.101578","source":"Crossref","is-referenced-by-count":2,"title":["Human cytomegalovirus infection coopts chromatin organization to diminish TEAD1 transcription factor activity"],"prefix":"10.7554","volume":"13","author":[{"given":"Khund","family":"Sayeed","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01hcyya48","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Autoimmune Genomics and Etiology, Division of Human Genetics, Cincinnati Children's Hospital Medical Center","place":["Cincinnati, United 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