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• W4386819355 abstract "Abstract Human cytomegalovirus (HCMV) is a prevalent pathogen that establishes life-long latent infection in hematopoietic cells. While this infection is usually asymptomatic, immune dysregulation leads to viral reactivation, which can cause significant morbidity and mortality. However, the mechanisms underpinning reactivation remain incompletely understood. The HCMV major immediate early promoter (MIEP)/enhancer is a key factor in this process, as its transactivation from a repressed to active state helps drive viral gene transcription necessary for reactivation from latency. Numerous host transcription factors bind the MIE locus and recruit repressive chromatin modifiers, thus impeding virus reactivation. One such factor is CCCTC-binding protein (CTCF), a highly conserved host zinc finger protein that mediates chromatin conformation and nuclear architecture. However, the mechanisms by which CTCF contributes to HCMV latency were previously unexplored. Here, we confirm CTCF binds two convergent sites within the MIE locus during latency in primary CD14 + monocytes, and following cellular differentiation, CTCF association is lost as the virus reactivates. While mutation of the MIE enhancer CTCF binding site does not impact viral lytic growth in fibroblasts, this mutant virus fails to maintain latency in myeloid cells. Furthermore, we show the two convergent CTCF binding sites allow looping to occur across the MIEP, supporting transcriptional repression during latency. Indeed, looping between the two sites diminishes during virus reactivation, concurrent with activation of MIE transcription. Taken together, our data reveal that three-dimensional chromatin looping aids in the regulation of HCMV latency, and provides insight into promoter/enhancer regulation that may prove broadly applicable across biological systems. Significance Statement Human cytomegalovirus (HCMV) remains an important healthcare consideration driven by disease in at-risk populations associated with reactivation of this virus from latent infection. We show here the establishment of latency is aided by a host nuclear architectural protein, CTCF. By binding two convergent sites on the virus major immediate early promoter/enhancer region, which largely acts as a switch from latency to reactivation, CTCF anchors a chromatin loop such that the virus promoter is maintained in a transcriptionally repressed state. Upon differentiation of cells, CTCF protein levels decrease, and this loop is alleviated as the virus reactivates. Our findings reveal further insight into the regulation of HCMV latency and promoter/enhancer elements, which is broadly applicable across biological systems." @default.
• W4386819355 created "2023-09-19" @default.
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• W4386819355 date "2023-09-18" @default.
• W4386819355 modified "2023-09-28" @default.
• W4386819355 title "Host-encoded CTCF regulates human cytomegalovirus latency via chromatin looping" @default.
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• W4386819355 doi "https://doi.org/10.1101/2023.09.18.557586" @default.
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