Discovering the Complete Enhancer Map of Human Herpesviruses Using a Natural Language Processing Model: supplemental files

Abstract Enhancers are distal cis-regulatory elements that dictate complex transcriptional repertoire. Herpes viruses show programmed latent and lytic gene expression based on the infected tissue and physiological cell state. Kaposi sarcoma-associated herpes virus (KSHV), an oncogenic dsDNA virus, possesses several enhancers that regulate latency and lytic gene expression. Here, we present a natural language processing model (NLP)-based tool, ENHAvir, that was trained with only six KSHV viral enhancer sequences and successfully predicted enhancer elements in other viruses and the human genome. ENHAvir identified known enhancers and predicted novel enhancer elements in the human herpes viruses; HSV-1, HSV-2, VZV, HCMV, HHV-6, HHV-7, and EBV. In the case of EBV, the activity of all predicted enhancers, BamHI-W repeats/BWRF1, BPLF-1, BALF-3, BKRF1, and terminal repeat (TR), was confirmed in enhancer reporter assay. The EBV TR presents features of a “viral super-enhancer” that is responsive to the viral activator ZTA and lytic inducers, suggesting a role in the latency to lytic transition. Interestingly, ENHAvir also precisely identified enhancers in the human genome. Once we obtained the enhancer sequences of all herpes viruses, we were able to compare them with human enhancers. This analysis revealed conserved enhancer signatures and the involvement of Alu elements. Zenodo contents This repository contains supplemental files of ENHAvir 2.0 training data, MEME analyses, and the phylogenetic tree raw file.