Orchestrated cellular gene expression in cells infected by adenovirus

Fluctuating expression of microRNAs in adenovirus infected cells

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Adenoviruses are wonderful study objects. They are beautiful to watch in the electron microscope and they infect human cells with an exceptional efficiently. Milligram quantities of pure virus can be obtained with insignificant efforts. Still, the virus usually treats its host mildly and many of the types prefer to stay dormant in our tonsils. For decades adenoviruses have severed as an outstanding model for studies of eukaryotic gene structure and expression. Moreover, their effect on host cells at the early after infection mimics tumorigenesis by promotion of cell growth and inhibition of apoptosis. Our surmise was that the adenoviruses will continue to provide important insights in how eukaryotic genes are regulated. Our story started with a study of the transcriptome in an adenovirus infected cell by using high-throughput technologies, first cDNA microarray analysis and subsequently deep sequencing technologies. Human primary lung fibroblasts were chosen as host as they should mimic a natural infection in humans. The adenovirus infectious cycle progresses slowly, thus providing a wide window for examination of gene expression changes during different phases of the infection. Our early transcriptome studies revealed that cellular gene expression is regulated in a stepwise manner. Target genes changed from those involved in the cell cycle, growth control, and antiviral response to genes required for DNA, RNA and protein synthesis, implying that the control of cellular gene expression is switched from the host cell to the virus.

The mechanism behind the deregulation of cellular gene expression was investigated by scanning for consensus binding sites for transcription factors in the affected genes. As microRNAs (miRNAs) are essential regulators of gene expression the cellular miRNA expression profile was examined in parallel with the mRNA profiles using deep sequencing. Similar to the expression of mRNA, the most significant changes in miRNA expression occurred at 24 hpi and most of the deregulated miRNAs turned out to be down-regulated. Furthermore, several miRNAs known as tumor suppressors are up-regulated, whereas miRNAs known to be oncogenic were down-regulated early in the infectious cycle. This expression pattern is switched when the virus takes over the control and miRNAs that function as tumor suppressors decrease rapidly, whereas expression of oncogenic miRNA increases dramatically. Our results show that adenoviruses use multiple mechanisms to fine-tune gene expression in their host.

Figure legend. Correlation of cellular mRNA and miRNA expression changes with the progression of adenovirus infection. A) Progression of adenovirus infection in human primary lung fibroblasts. E1A and cyclin E1 represent the changes of their RNA levels; Ad-DNA indicates the kinetics of adenovirus DNA replication. B) Hierarchical clustering analysis of the cellular miRNA expression profile. C) Hierarchical clustering analysis of cellular mRNA expression profile.

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Introducing the Authors

PIC

Prof. Ulf Pettersson (left), Dr. Hongxing Zhao (middle) and Maoshan Chen (right).

About the research
Fluctuating expression of microRNAs in adenovirus infected cells
Virology, Volume 478, April 2015, Pages 99–111
Hongxing Zhao, Maoshan Chen, Christian Tellgren-Roth, Ulf Pettersson

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