Journal article
Cell type differences in human cytomegalovirus transcription and epigenetic regulation with insights into major immediate-early enhancer-promoter control
PLoS pathogens, Vol.21(8), e1013374
08/04/2025
DOI: 10.1371/journal.ppat.1013374
PMCID: PMC12333995
PMID: 40758707
Abstract
Cell type differences in the human cytomegalovirus (HCMV) transcriptome may arise from variations in transcription or post-transcription regulation. Here we report unexpected differences in transcription and epigenetic control in late-stage HCMV infection of human differentiated NTera2 neural lineage cells (D-NT2) compared to fibroblasts, using integrated functional genomic approaches (PRO-Seq, RNA-Seq, DNA fragmentation factor-ChIP Seq, rapid viral protein degradation, and promoter mutation and function assays). In D-NT2, but not fibroblasts, RNA polymerase II initiation and elongation at several viral promoters requires viral DNA synthesis and are independent of host P-TEFb, viral immediate-early protein 2 (IE2), or viral late transcription factor (LTF). This includes transcription from the enhancer for the major immediate early (MIE) promoter where GC-box sequence mutations increase enhancer transcription, while mutations in CREB and NF-kB response elements reduce it. The GC-box mutations also alter infected D-NT2 cell morphology and gene expression program without affecting viral MIE gene expression levels, whereas mutations in CREB and NF-kB response elements do not induce these changes. In D-NT2, LTF-driven promoters constitute a smaller proportion of the viral late promoter population and are generally less active. Additionally, viral genomes have more nucleosomes, potentially restricting LTF access. A TATA-binding protein (TBP)-IE2-nucleosome complex, with more nucleosome than in fibroblasts, occupies the MIE promoter transcription start site, potentially contributing to its epigenetic silencing.
Details
- Title: Subtitle
- Cell type differences in human cytomegalovirus transcription and epigenetic regulation with insights into major immediate-early enhancer-promoter control
- Creators
- Qiaolin Hu - University of IowaMing Li - University of Iowa, Internal MedicineMrutyunjaya Parida - University of IowaBenjamin M Spector - University of IowaJuan F Santana - University of IowaArya Zandvakili - University of IowaDavid H Price - University of IowaJeffery L Meier - Iowa City VA Health Care System
- Resource Type
- Journal article
- Publication Details
- PLoS pathogens, Vol.21(8), e1013374
- DOI
- 10.1371/journal.ppat.1013374
- PMID
- 40758707
- PMCID
- PMC12333995
- NLM abbreviation
- PLoS Pathog
- ISSN
- 1553-7366
- eISSN
- 1553-7374
- Publisher
- PUBLIC LIBRARY SCIENCE
- Grant note
- National Institute of Allergy and Infectious Diseases: R21 AI130453, 5T32AI007343-35 National Institute of Allergy and Infectious Diseases: I01 BX004434 Department of Veterans Affairs Merit award
This research was supported by the National Institute of Allergy and Infectious Diseases (R21 AI130453 to DHP and JLM, and 5T32AI007343-35 to AZ), and by The Department of Veterans Affairs Merit award (I01 BX004434 and SeqCure Network to JLM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- Language
- English
- Date published
- 08/04/2025
- Academic Unit
- Infectious Diseases; Epidemiology; Pathology; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984945088502771
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