Cytomegalovirus Late Transcription Factor Target Sequence Diversity Orchestrates Viral Early to Late Transcription

Herpesviruses have a group of genes earmarked for expression late in the infection. Beta- and gammaherpesviruses utilize a six-member set of viral late transcription factors to selectively activate these genes by binding to a DNA sequence signature in gene promoters. We made an unexpected discovery that differences in sequence signature configures the late gene expression program for human cytomegalovirus, a beta-herpesvirus of global public health importance. Diversity in signature patterns expands promoter targets and pre-sets amount of individual promoter output. A unique palindromic sequence signature is linked to the activation of back-to-back promoters at multiple locations in the viral genome. We deduce that diversity in late transcription factor targets functionally orchestrates the productive rollout of the late-stage infection. This may be a generalizable feature adopted by beta- and gammaherpesvirus subfamilies. Overall design: In this study, we assessed the effects of LTF (UL87 and UL79) depletion in late HCMV infection. We analyzed 20 PRO-Seq datasets and 4 ChIP-seq datasets from HFF that were infected with HCMV strains Towne or TB40/E. We show that the effects LTF depletion on viral gene transcription are reproduced in the content of infection with different HCMV strains. Replicate analyses of the effects of LTF depletion were performed.