Tracing functional (epi)genomic imprints and their evolutionary origins in human defense antiviral cellular response (STARR-transcripts-Seq)

An integral part of human cellular homeostasis substantially relies on defense transcriptional responses tailored to fight microbial pathogens, including Viruses. However, a definitive anatomy of the “virus-responsive” fates of the non-coding genome was largely elusive. Here, we exhaustively assayed the human transcriptome and epigenome under naïve and antiviral cellular states and defined remarkable reprogramming to mark the exchange of cellular fates, involving previously unspecified, unsupervised, or overlooked non-coding entities endowed with thousands of novel virus-responsive enhancers, Super-enhancers (SEs), and Repetitive DNA enhancers. These functional determinants demonstrate superior chromatin architecture, stimulus-specificity, and transcriptional fitness, and neighbor, reside proximal, or entirely coincide with hundreds of the virus-stimulated genes, while a multitude of those is bound by the master antimicrobial TFs, IRF3 or/and NFκB, upon cell infection. A plethora of these DNA elements is traced within the repetitive fate of the human genome including Simple Tandem Repeats (STRs), Dispersed Repeats (DRs) such as retrotransposons and DNA transposons, and chimeras of those, enriched in HCTFBSs recognized by IRF3 or/and NFκB and exhibits pervasive imprints in the genomes of evolutionary recent, old and ancient species, including viruses. These findings emphasize the role of the architectural and functional compartmentalization of the human epigenome in naïve and infected cells on the perplexing natural conflicts and mechanistic dependencies that impose the frontage of defense gene expression in humans.