We explore the functions of transposons through studying their dynamic epigenetic regulation
Over half of our DNA is referred to as “dark matter” because its function is largely unknown. Most of this DNA is derived from transposons, which can be regarded as remnants of ancient viruses that once replicated. However, while a few transposons such as LINE-1 elements can still move within our genome, the majority are no longer mobile, due to genetic drift. Retrotransposons represent one class of transposons that replicate through a copy-and-paste mechanism and have expanded in the human and mouse genome. Transposons, as part of our DNA, are stably inherited from one generation to the next and have co-evolved with their hosts for millions of years.
Snapshots of transposon-host interactions
Have you ever wondered what the function of this dark matter is? In the Rowe Lab, we focus on snapshots of transposon-host epigenetic interactions in order to dissect the functions of some of the dark matter within our genome. We have selected transposons that are targeted by host transcription factors because these are most likely to have been co-opted to perform important functions for their hosts. We are mainly interested in zinc finger proteins, which exhibit sequence-specific binding of transposon-derived DNA. We are passionate about understanding how some of these transposons have been coerced to play normal roles in gene regulation and how they could be involved in diseases ranging from cancer to auto-inflammatory disease.
Transposons as regulatory hubs and immune messengers
We and others have discovered that transposons often have intact regulatory elements such as enhancers, promoters or silencers so are perfectly poised to regulate cellular genes and contribute to the formation of new genes. Early in development, epigenetic pathways act to mediate transcriptional silencing of transposon-derived sequences and involve KRAB-zinc finger proteins, KAP1/TRIM28 and the HUSH complex. As a secondary effect of their suppression of transposons, these epigenetic pathways have evolved to regulate cellular genes in their vicinity. Furthermore, transposons can play structural roles in nuclear organization and gene regulation because they act as focal points for silent chromatin formation, termed heterochromatinization. We have set out to discover which cellular genes and processes are regulated by transposon-regulatory hubs, and through which epigenetic factors. Recently, we and others have found that once epigenetic repression is relieved, transposons can produce nucleic acids that may be sensed as non-self by the immune system. This suggests that transposon-derived nucleic acids may act as immune messengers that potentially mediate cross-talk with innate and adaptive immunity through their induction of interferons.
This is a fast-moving and exciting field in which to work because collectively groups that work in this area are on the verge of discovering exactly how transposons control cell fate and fuel the immune system. This will shed light on how transposons potentially contribute to developmental or auto-inflammatory diseases when errors in their regulation ensue.