The making of more powerful stem cells
Transposable elements have been inserting new copies of themselves into our genome for millions of years, and today they form a large part of our DNA, yet relatively little is known about them. While most of these transposable elements are no longer mobile, some have the power to immortalize cells by remodelling the genome, as Dr Helen Rowe explains. Around half
of the human genome is made up of transposable elements, including both retrotransposons and DNA transposons, which can be thought of as ancient viruses because they once replicated and inserted new copies of themselves into the genomes of our ancestors. While these elements are abundant in the genome (around half of our DNA), relatively little is known about them. “We don’t really know what’s in there as they are poorly characterised, and we know even less about their function,” says Dr Helen Rowe, Senior Lecturer in Epigenetics at Queen Mary University of London (QMUL). Retrotransposons replicate through an RNA intermediate, an RNA molecule, which is an important difference with DNA transposons. “They can reverse transcribe their RNA into DNA, which means that they can readily expand their copy number by making new copies of themselves to insert at new locations throughout the genome,” explains Dr Rowe. Although these ancient viruses are no longer mobile, many have retained fragments called ‘enhancers’ that can switch on expression of our own genes.
Genome remodelling As the Principal Investigator of an EU-funded project based at QMUL, Dr Rowe aims to shed new light on the role of retrotransposons in
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genome remodelling, using embryonic stem cells from mice as a model system. In earlier research, Dr Rowe investigated an epigenetic regulation pathway of these transposable elements. “We know the components of that pathway are transcription factors, proteins that bind to DNA sequences embedded in these retrotransposons. This is a novel class of transcription factors that are still mostly uncharacterised,” she
the mouse genome. Researchers are using a technique called CRISPR/Cas9 to edit the genome. “We can basically edit the DNA responsible for making these ZFPs, thereby preventing their function by generating a gene ‘knockout’. This approach helps us to dissect the function of the retrotransposons that these ZFPs bind to and usually switch off,” explains Dr Rowe.
We’re looking at zinc finger proteins that alter the chromatin landscape, and they bind to specific DNA sequences embedded within retrotransposons. We can map their binding sites using chromatin profiling techniques such as ‘Chromatin Immunoprecipitation-sequencing’ and ‘CUT&RUN’. outlines. Dr Rowe and her colleagues have been studying this novel class of proteins – called zinc finger proteins (ZFPs) – which could lead to new insights into the functions of some of these transposable elements. “A huge number of those ZFPs are encoded by the human and mouse genome,” she says. A very small proportion of these ZFPs have been characterised, a topic at the heart of the project’s overall agenda. The Rowe lab are focusing on ZFPs that bind to retrotransposons that are present at hundreds of copies in
The focus of attention here is on two specific transcription factors, ZFP37 and ZFP819. “We’ve got one PhD student, Liane Fernandes leading the project on ZFP819, and a Postdoctoral Fellow, Poppy Gould leading the project on ZFP37,” continues Dr Rowe. A second Postdoctoral Fellow, Rocio Enriquez-Gasca, is working on both projects, pioneering novel computational pipelines, which are essential to the analysis of sequence data derived specifically from retrotransposons. “We can specifically target the genes that encode those proteins
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