Human cytomegalovirus infects more than half of humans, persists silently in virtually all tissues, and produces life-threatening disease in immunocompromised individuals. HCMV is also the most common infectious cause of birth defects and the leading nongenetic cause of sensorineural hearing loss in the United States. Because there is no vaccine and current drugs have problems with potency, toxicity, and antiviral drug resistance, alternative treatment strategies that target different points of viral control are needed. Our current study contributes to this goal by applying newly developed methods to examine transcription of the HCMV and host genomes at nucleotide resolution in an attempt to find targetable differences between the two. After a thorough analysis of productive elongation and of core promoter element usage, we found that some mechanisms of regulating transcription are shared between the host and HCMV but that others are distinctly different. This suggests that HCMV transcription may be a legitimate target for future antiviral therapies and this might translate to other herpesviruses.
The core histone tails are critical in chromatin structure and signaling. Studies over the past several decades have provided a wealth of information on the histone tails and their interaction with chromatin factors. However, the conformation of the histone tails in a chromatin relevant context has remained elusive. Only recently has enough evidence emerged to start to build a structural model of the tails in the context of nucleosomes and nucleosome arrays. Here, we review these studies and propose that the histone tails adopt a high-affinity fuzzy complex with DNA, characterized by robust but dynamic association. Furthermore, we discuss how these DNA-bound conformational ensembles promote distinct chromatin structure and signaling, and that their fuzzy nature is important in transitioning between functional states. Highlights Eukaryotic DNA is wrapped around histone proteins to form nucleosomes that fold into higher-order chromatin structures, and the local chromatin structure regulates all DNA-templated processes. All core histone proteins contain intrinsically disordered tail regions that protrude from the DNA-wrapped core and are known to be critical in chromatin regulation. Recent studies have revealed that the core histone tails adopt multiple conformations on the nucleosomal and linker DNA; these tail/DNA interactions are robust, but exchange quickly between multiple conformations consistent with a so-called fuzzy complex. Intra-versus inter-nucleosome contacts by the tails differentially contribute to the local chromatin state and thus regulation of DNA-templated processes. Histone post-translational modifications and chromatin-associated factors can modulate these fuzzy conformational ensembles and tail accessibility, indicating that the tail/DNA interactions are an important regulatory mechanism of chromatin.
Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized "codes" that are read by specialized regions (reader domains) in chromatin associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP-histone PTM] specificity, and thus decipher the histone code / guide epigenetic therapies. However, this has largely been done using a reductive approach of isolated reader domains and histone peptides, with the assumption that PTM readout is unaffected by any higher order factors. Here we show that CAP-histone PTM interaction is in fact dependent on nucleosome context. Our results indicate this is due to histone tail accessibility and the associated impact on binding potential of reader domains. We further demonstrate that the in vitro specificity of a tandem reader for PTM-defined nucleosomes is recapitulated in a cellular context. This necessitates we refine the "histone code" concept and interrogate it at the nucleosome level.
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