Human cytomegalovirus infection coopts chromatin organization to diminish TEAD1 transcription factor activity

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Abstract
Human cytomegalovirus (HCMV) infects up to 80% of the world’s population. 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 TEAD1 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’s established roles in these processes.
Funding Information
  • National Institutes of Health (R01 HG010730)
  • National Institutes of Health (R01 GM055479)
  • National Institutes of Health (U01 AI130830)
  • National Institutes of Health (R01 AR073228)
  • National Institutes of Health (R01 NS099068)
  • National Institutes of Health (R01 AI024717)
  • National Institutes of Health (R01 AI148276)
  • National Institutes of Health (U01 HG011172)
  • National Institutes of Health (U19 AI070235)
  • National Institutes of Health (P30 AR070549)
  • National Institutes of Health (T32 ES007250)
  • National Institutes of Health (R21 DE026267)
  • National Institutes of Health (R01 AI121028)
  • National Institutes of Health (F32 AI172329)
  • National Institutes of Health (T32 AI007245)
  • National Institutes of Health (R01 AI164709)
  • U.S. Department of Veterans Affairs (I01 BX003850)
  • U.S. Department of Veterans Affairs (I01 BX001834)
  • U.S. Department of Veterans Affairs (I01 BX006254)

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