New study shines light on beneficial and pathogenic elements of ‘genomic dark matter’
A new study published in Cell Reports reveals certain elements of ‘genomic dark matter’ known as transposable elements as either beneficial or harmful to our health, exploring why this is and paving the way for future understanding of how to combat malignant cancers and other human diseases.
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Members of the Rowe Lab at the Blizard Institute. From left: Rocio Enriquez-Gasca (first), Helen Rowe (third) and Poppy Gould (fourth).
The research, led by Rocio Enriquez-Gasca and Poppy Gould from the Blizard Institute and funded through a European Research Council starting grant, looks at elements of our DNA with an unknown function, most of which is comprised of what are known as transposable elements.
Less than two percent of the human genome comprises genes and most of the rest is referred to as genomic dark matter. Much of this dark matter is derived from transposable elements, which were once mobile genetic elements that have now largely lost their ability to jump, due to mutations.
This part of our genome is a blind spot in our understanding, as it is difficult to study due to these sequences being repetitive. Recent evidence has shown that dark matter contributes to health and disease processes, including immunity to pathogens, as well as contributing to diseases such as cancers. There has been little information or understanding, however, about which transposable elements within the depths of dark matter are important.
This study used mouse development as a model and showed some surprising findings. Although a huge proportion of transposable elements get switched off (to prevent their expression) through epigenetic mechanisms, these pathways are targeted towards the most pathogenic genomic copies, some of which can still jump.
The researchers also revealed a novel epigenetic pattern of silencing of these transposable elements in neural progenitor cells. The researchers also showed transposable elements in the brain have escaped epigenetic repression and adopted beneficial roles in host gene regulation.
This work provides insight into some recent findings showing that in cancers, there is frequent jumping (retrotransposition) of transposable elements, which contributes to the evolution and malignancy of the tumour. Certain cancers have a particularly high rate of retrotransposition, for example lung cancers.
This work has pinpointed epigenetic silencing in being targeted towards transposable elements, which are still capable of jumping. Taken together, these results suggest that high rates of retrotransposition in cancers could be linked to prior loss of epigenetic regulation of the pathways that the researchers have uncovered. This knowledge will help us to better understand and combat malignant tumours.
Dr Helen Rowe, Senior Lecturer in Epigenetics at the Blizard Institute, said: “The study represents a conceptual advance in our understanding of the co-evolution of transposable elements with our genome surveillance pathways. It also provides a framework for future studies invested in understanding the beneficial and pathogenic roles of transposable elements further, with the long-term goal to harness dark matter to combat cancer and other diseases.”
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The Rowe Lab is interested in characterising dark matter with the goal to translate this knowledge into new therapies. The funding from the European Research Council (ERC) starting grant awarded to Dr Helen Rowe funded the joint first authors, Rocio Enriquez-Gasca and Poppy Gould. With their inclusive vision for women in science, the ERC allows scientists extra time to apply for these grants if they have taken time out of research to have children. This work also involved collaborations with investigators at University College London, Glasgow University and the Jackson Laboratory for Genomic Medicine, USA.