While less than 2% of our DNA codes for proteins, more than half is made up of repetitive elements or simply ‘repeats’. These are often dynamic stretches of DNA, some of which can copy or move themselves around the human genome. Repeats are a principal source of genetic diversity, but when their regulation fails, they can interrupt important genomic functions and contribute to diseases that affect the nervous system including Huntington’s disease, Fragile X syndrome, and X-linked Dystonia-Parkinsonism (XDP) – so-called ‘repeat disorders’.
“Getting to the root cause of how repeats are controlled and influence gene regulation is what drives my curiosity,” Christopher Douse says.
“Repetitive DNA sequences are the most dynamic sequences in our genomes, and when the mechanisms to control those dynamics fail, it often causes severe problems for human health. We want to understand what those fundamental mechanisms are that control repeats, and what happens when these mechanisms break down.”
Getting to the root of repeat-associated disorders
“If you ask clinicians and scientists who study repeat disorders the simple question, ‘why do these disorders commonly affect the nervous system?’ surprisingly, no one really has a good answer,” explains Christopher. “That is the big question now driving our work. My hypothesis is that the answer may lie in the epigenome, the layer of molecular information that controls how our genes are switched on or off.”
Christopher Douse and his team are investigating how the repetitive regions of the human genome, sometimes called ‘genomic dark matter,’ are controlled by the epigenome and chromatin - the tightly packed structure that organizes DNA, RNA, and proteins within the cell nucleus.
His research programme will build on his group’s earlier support from the Chan Zuckerberg Initiative, which allowed the team to develop a unique technology linking the epigenome to gene activity within repetitive DNA sequences, in cellular models of the human nervous system. With the new SSMF grant, the researchers can now apply this tool to explore how failures in epigenetic regulation could contribute to repeat disorders.
“We also want to know if these mechanisms work similarly across the diverse spectrum of repeat disorders. If we can start to answer that, we will be much closer to identifying where and how to intervene therapeutically,” he points out. “It has never been more important to understand these fundamental mechanisms to make the right choice from today’s ‘therapy’ toolbox, whether that is a cell or gene therapy, small molecule or another modality.”
An interdisciplinary approach to better understand the genome’s dark matter
To do address these questions, the lab works closely with colleagues in neurobiology and stem cell research at Lund University and internationally through networks established through the Chan Zuckerberg Initiative and other consortia. “This work is a real team effort and requires close collaboration between laboratory scientists and bioinformaticians,” Christopher highlights. “Our focus is on fundamental, mechanistic research. We can only answer these more translational questions because we are connected to international networks and embedded in an environment rich in expertise in stem cell and neurobiology. That mix is what makes Lund an ideal place to do this work.”
Funding new discoveries in medical research for the long-term
As one of the few five-year grants in Sweden, the SSMF award gives Christopher and his team the opportunity to tackle this ambitious line of research. “Five years gives you space to build a new direction of research and security to plan for the long term. This is something that’s hard to do in science today, especially with the challenging economic conditions here and abroad.”
He notes that the grant comes at an important time: “To answer big scientific questions, you need stable resources, which has been hard for universities to provide. Constantly applying for new funding is draining and shortens your horizon. Longer term support allows us to think beyond the next paper, and quite simply do better science.”
For Christopher Douse, the SSMF award also marks a full-circle moment. His first grant was an SSMF Starting Grant, which enabled him to establish his independent research programme in Lund in early 2020.
“I do not think I would be where I am today without the support of SSMF,” he emphasises. “Their support gave me my start 5 years ago, and now this gives us the chance to grow further, expand the team and pursue our research for the long term.”