
==== Front
bioRxiv
BIORXIV
bioRxiv
Cold Spring Harbor Laboratory

38645179
10.1101/2024.04.12.588762
preprint
3
Article
Human cytomegalovirus infection coopts chromatin organization to diminish TEAD1 transcription factor activity
Sayeed Khund
Parameswaran Sreeja
Beucler Matthew J.
Edsall Lee E.
VonHandorf Andrew
Crowther Audrey
Donmez Omer
Hass Matthew http://orcid.org/0000-0001-9507-4333

Richards Scott
Forney Carmy
Wright Jay
Leong Merrin Man Long
Murray-Nerger Laura A.
Gewurz Ben E.
Kaufman Kenneth M.
Harley John B.
Zhao Bo
Miller William E.
Kottyan Leah C. http://orcid.org/0000-0003-3979-2220

Weirauch Matthew T. http://orcid.org/0000-0001-7977-9122

22 5 2024
2024.04.12.588762http://biorxiv.org/lookup/doi/10.1101/2024.04.12.588762
nihpp-2024.04.12.588762.pdf
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 hours 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.
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pmc
