Characterization of influenza A virus induced transposons reveals a subgroup of transposons likely possessing the regulatory role as eRNAs

Steven S Shen,Ryan A Langlois,Hezkiel Nanda,Constantin Aliferis

doi:10.1038/s41598-022-06196-6

Steven S Shen, Ryan A Langlois + Show 2 more

Open Access

https://doi.org/10.1038/s41598-022-06196-6

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Abstract

Although many studies have observed genome-wide host transposon expression alteration during viral infection, the mechanisms of induction and the impact on the host remain unclear. Utilizing recently published influenza A virus (IAV) time series data and ENCODE functional genomics data, we characterized virus induced host differentially expressed transposons (virus-induced-TE) by investigating genome-wide spatial and functional relevance between the virus-induced-TEs and epigenomic markers (e.g. histone modification and chromatin remodelers). We found that a significant fraction of virus-induced-TEs are derived from host enhancer regions, where CHD4 binding and/or H3K27ac occupancy is high or H3K9me3 occupancy is low. By overlapping virus-induced-TEs to human enhancer RNAs (eRNAs), we discovered that a proportion of virus-induced-TEs are either eRNAs or part of enhancer RNAs. Upon further analysis of the eRNA targeted genes, we found that the virus-induced-TE related eRNA targets are overrepresented in differentially expressed host genes of IAV infected samples. Our results suggest that changing chromatin accessibility from repressive to permissive in the transposon docked enhancer regions to regulate host downstream gene expression is potentially one of the virus and host cell interaction mechanisms, where transposons are likely important regulatory genomic elements. Our study provides a new insight into the mechanisms of virus-host interaction and may lead to novel strategies for prevention and therapeutics of IAV and other virus infectious diseases.

Highlights

We recently demonstrated that host transposon element (TE) expression is largely impacted by viral infection[1]
These interesting findings are suggestive of possible gene expression regulation roles by TE transcripts, which prompted our investigation into the genomic spatial relationship between the virus-induced-TE and permissive and/or repressive epigenomic markers, such as histone markers, chromatin remodelers, and transcription factors
To understand the potential functional role of virus-induced-TEs in the host, we carefully examined the genomic loci of influenza A virus (IAV)-induced-TEs to known enhancer RNAs

Summary

Introduction

We recently demonstrated that host transposon element (TE) expression is largely impacted by viral infection[1]. Et al reported that the connection between TEs and histone markers may impact gene expression regulation[7] These interesting findings are suggestive of possible gene expression regulation roles by TE transcripts, which prompted our investigation into the genomic spatial relationship between the virus-induced-TE and permissive and/or repressive epigenomic markers, such as histone markers, chromatin remodelers, and transcription factors. We introduce a new virus-host interaction model, showing that viruses likely influence host gene expression by activating poised enhancers and promoting eRNA transcription, where host TEs may play complex roles in the virus host interaction and gene expression regulation This model is based on IAV but may apply to other RNA viruses including SARS-CoV-2, RSV and HPIV3. Our discovery provides new insight into the mechanisms of virus-host interaction and may lead to novel preventive and therapeutic targets for IAV and other RAN virus infection diseases

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