GSE208716
Adenovirus small E1A directs activation of Alu transcription at YAP/TEAD- and AP-1- bound enhancers through interactions with the EP400 chromatin remodeler [RNA-Seq]
Alu retrotransposons, forming the largest family of mobile DNA elements in the human genome, have recently come to attention as a potential source of regulatory novelties, most notably by participating in enhancer function. Even though Alu transcription by RNA polymerase III is subjected to tight epigenetic silencing, their bulk expression has long been known to increase in response to various types of stress, including viral infection. Here we show that, in primary human fibroblasts, adenovirus small e1a triggered derepression of hundreds of individual Alus, by promoting TFIIIB recruitment by Alu-bound TFIIIC. Epigenome profiling revealed an e1a-induced decrease of H3K27 acetylation and increase of H3K4 monomethylation at derepressed Alus, making them resemble poised enhancers. The enhancer nature of e1a-targeted Alus was confirmed by the enrichment, in their upstream regions, of the EP300/CBP acetyltransferase and of the YAP1 and FOS transcription factors. The physical interaction of e1a with the chromatin remodeler EP400 turned out to be critical for Alu derepression, and upstream enrichment of EP400 was found to commonly demarcate expression-prone Alus. Our data suggest that e1a targets a subset of enhancer Alus whose transcriptional activation, mediated by e1a-EP400 interaction, may participate in the manipulation of enhancer activity by adenovirus. Overall design: Total RNA-seq of G1-arrested IMR90 cells infected with HAdV-C5 mutant dl1500 (which expresses the immediate early protein E1A with little or no expression of other viral genes), versus infection with HAdV-C5 mutant dl312, with deletion of the complete E1A coding region. Mock-infected cells taken through the same changes in medium, but without addition of virus, served as a further control. The experiment was performed in duplicate. A second round of total RNA-seq was performed in G1-arrested IMR90 cells infected with HAdV-C5 mutant strains expressing e1a mutants that are impaired in the ability to interact with either RB-family proteins, EP300 and its paralog CREB Binding Protein (CREBBP), or EP400, compared to cells infected in parallel with mock- or dl1500. The experiment was performed in triplicate, exept for RB binding mutant, which was performed in duplicate.