Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Exhibit Hall E
Background: Reactivation of latent CMV is a significant infectious complication in solid organ transplant recipients. MCMV is a valuable model for studying molecular mechanisms controlling latency and reactivation in vivo. Our previous studies showed that 1) viral gene expression is repressed in MCMV latent mice through heterochromatinization of viral genomes; 2) reactivation of immediate early (IE) gene expression can be induced within 48 hr by allogeneic transplantation of latent kidneys. Activation of IE gene expression is a critical first step in reactivation of the virus. Here we have analyzed changes in the viral epigenome in this model. Changes in cellular transcription factors that control viral IE gene expression, including NF-kB and AP-1, and cellular RNA expression were analyzed to identify potential mechanisms driving reactivation.
Methods: Kidneys from latently infected mice were transplanted into allogeneic recipients, and analyzed for transcription factor activation at 3, 24, and 48 hr, and for changes in cellular gene expression and viral chromatin at 48 hr.
Results: Several members of the AP-1 and NF-kB family were activated within 3 hr after transplant, and some components remained active up to 48 hr. Analysis of cellular gene expression showed that many AP-1- and NF-kB-responsive genes were up-regulated at 48 hr post-transplant. Chromatin immunoprecipitation assays showed that allogeneic transplantation induced major changes in viral chromatin in the IE region, including loss of repressive histone modifications, and gain of euchromatic histone modifications. Several transcriptional regulatory factors were recruited to the major immediate early promoter, including RNA polymerase II, NF-kB p65, AP-1 junD, and beta-actin, a component of nucleosome remodeling complexes. Pathway analysis of changes in cellular gene expression identified several inflammatory signaling pathways that were significantly up-regulated.
Conclusions: Transcriptional reactivation of the IE genes in Day 2 allogeneic transplants is associated with epigenetic reprogramming of viral chromatin. We have identified signaling pathways that may contribute to transcriptional reactivation of the IE genes, and thus, to reactivation of virus in immunocompromised transplant recipients.
To cite this abstract in AMA style:Hummel M, Liu X-F, Jie C, Zhang Z, Yan S, Wang J-J, Kurian S, Salomon D, Abecassis M. Epigenetic Reprogramming of Murine Cytomegalovirus Immediate Early Genes Induced By Renal Transplantation [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/epigenetic-reprogramming-of-murine-cytomegalovirus-immediate-early-genes-induced-by-renal-transplantation/. Accessed July 30, 2021.
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