Endogenous Retroelements As Transcriptional Parasites And Modulators Of Host Immunity

Introduction

Almost half of our genome is occupied by ancient viral sequences that can be mobilized under certain conditions and either jump or copy themselves from one location to another. A group of these mobile genetic elements is called endogenous retroelements.

Impact of Retroelements

Mobilization of retroelements like LINE1 has been shown to cause cancer via insertional mutagenesis. In recent years, LINE1 activation has also been associated with the development of inflammatory diseases and inflammation-driven ageing. This means we have collected substantial evidence that half of our genome can potentially make us sick.

Evolutionary Perspective

Nevertheless, we keep replicating these sequences with every cell division at great energetic cost, suggesting that keeping them provides an evolutionary advantage.

Project Goals

In my project, I will investigate if sporadic retroelement transcription in healthy cells serves a physiological role in priming the immune system through the constant sensing of retroelement-derived nucleic acids by intracellular nucleic acid sensors.

Research Focus

My team and I will investigate how retroelement transcription is regulated in response to daily life stresses like:

1. Virus infections
2. DNA damage

I propose that instead of regulating transcription themselves, retroelements are largely regulated by canonical gene expression.

Methodology

In mouse models, we will investigate how retroelements are sensed by the innate immune system and if this has functional consequences for establishing protective and pathologic immunity. Furthermore, we will investigate the exact molecular mechanism by which retroelement-derived single-stranded cDNA activates the innate immune system, which is currently not understood.

Development of New Techniques

Our project involves the development of:

• A new deep sequencing workflow for identification of the genomic origin of retroelement transcripts
• A new mouse model to study endogenous LINE1 elements in vivo

Conclusion

I believe that my project can fundamentally change our view on the role of endogenous retroelements as modulators of host immunity.