Dataset Information

Systems biology decodes herpes simplex virus 1

ABSTRACT: Since the genome of herpes simplex virus 1 (HSV-1) was first sequenced more than 30 years ago, the 84 genes it was thought to encode have been intensively studied. Here, we unravel the full complement of viral transcription and translation during lytic infection with base-pair resolution by computational integration of multi-omics data. This includes a total of 201 viral transcripts and 296 open reading frames (ORFs), comprising all known large ORFs, 55 large novel ORFs including a novel spliced ORF in the ICP0 locus that initiates from a non-AUG start codon and a novel strongly translated ORF in the ICP34.5 locus as well as multiple short ORFs. By defining viral gene modules, we link translation of ORFs to the expression of transcript isoforms. This explained translation of the vast majority of viral ORFs as well as N-terminal extensions and truncations thereof. We show that N-terminal extensions initiating from non-AUG start codons govern subcellular protein localization and packaging of key viral regulators and structural proteins. This work has great implications for future functional studies, vaccine design and novel oncolytic therapies.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Herpes Simplex Virus Unknown Type Homo Sapiens (human)

TISSUE(S): Fibroblast Of Lung

SUBMITTER: Guido Mastrobuoni

LAB HEAD: Stefan Kempa

PROVIDER: PXD013407 | Pride | 2020-05-22

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Toni_20130527_AE_Exp87_sample11_01.raw	Raw
	Toni_20130527_AE_Exp87_sample11_02.raw	Raw
	Toni_20130531_AE_Exp87_rep2_sample11_01.raw	Raw
	Toni_20130531_AE_Exp87_rep2_sample11_02.raw	Raw
	Toni_20130603_AE_Exp87_rep3_sample11_01.raw	Raw

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Publications

Integrative functional genomics decodes herpes simplex virus 1.

Whisnant Adam W AW Jürges Christopher S CS Hennig Thomas T Wyler Emanuel E Prusty Bhupesh B Rutkowski Andrzej J AJ L'hernault Anne A Djakovic Lara L Göbel Margarete M Döring Kristina K Menegatti Jennifer J Antrobus Robin R Matheson Nicholas J NJ Künzig Florian W H FWH Mastrobuoni Guido G Bielow Chris C Kempa Stefan S Liang Chunguang C Dandekar Thomas T Zimmer Ralf R Landthaler Markus M Grässer Friedrich F Lehner Paul J PJ Friedel Caroline C CC Erhard Florian F Dölken Lars L

Nature communications 20200427 1

The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcr ...[more]

PMID: 32341360

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Project description:Translation of an mRNA in eukaryotes starts at AUG in most cases. Near-cognate codons (NCCs) such as UUG, ACG and AUU are also used as start sites at low levels in S. cerevisiae. Initiation from NCCs or AUGs in the 5’-untranslated regions (UTRs) of mRNAs can lead to translation of upstream open reading frames (uORFs) that might regulate expression of the main ORF (mORF). Although there is some circumstantial evidence that the translation of uORFs can be affected by environmental conditions, little is known about how it is affected by changes in growth temperature. Using reporter assays, we found that changes in growth temperature can affect translation from NCC start sites in yeast cells, suggesting the possibility that gene expression could be regulated by temperature by altering use of different uORF start codons. Using ribosome profiling, we provide evidence that growth temperature regulates the efficiency of translation of nearly 200 uORFs in S. cerevisiae. Of these uORFs, most that start with an AUG codon have increased translational efficiency at 37 ˚C relative to 30 ˚C and decreased efficiency at 20 ˚C. For translationally regulated uORFs starting with NCCs, we did not observe a general trend for the direction of regulation as a function of temperature, suggesting mRNA-specific features can determine the mode of temperature-dependent regulation. Consistent with this conclusion, the position of the uORFs in the 5’-leader relative to the 5’-cap and the start codon of the main ORF correlates with the direction of temperature-dependent regulation of uORF translation. We have identified several novel cases in which changes in uORF translation are inversely correlated with changes in the translational efficiency of the downstream main ORF. Our data suggest that translation of these mRNAs is subject to temperature-dependent, uORF-mediated regulation. Overall, our data suggest that alterations in the translation of specific uORFs by temperature can regulate gene expression in S. cerevisiae.