Unveiling the epigenetic switches behind immune responses
Our immune system protects us from infections, thanks to the actions of the specialised cells it contains. However, disruptions to gene expression in immune cells mean that sometimes they do not function as they should. At McGill University in Canada, Professor David Langlais and his team are studying how the epigenome regulates which genes are expressed, and what happens when this does not go to plan.
Talk like a genomicist
Autoimmune disease — a condition in which the immune system attacks healthy cells
Epigenetic — how cells influence gene expression without changing the genetic code
Epigenome — the chemical modifications in a cell that affect gene expression
Genome — the complete set of genetic material in an organism
Gene — an element in the genome that is transcribed in an RNA molecule, sometimes coding for proteins
Multiomic — a research approach that combines data from multiple ‘omic’ (e.g., genomic, epigenomic) techniques
Pathogen — a microorganism that causes disease
Stem cell — a cell with the potential to differentiate into different types of cells
Transcription factor — a protein that regulates gene expression by binding to specific DNA sequences
As every cell in your body contains the same genetic code, why do your cells have such varied forms and functions? The answer lies in your epigenome – the complex array of chemical interactions that govern which genes are expressed and when. “Similar to how a recipe defines the types and quantities of ingredients for a meal, our body uses specific ingredients (genes) combined in precise quantities (gene expression level) to create different cell types and adapt them to their environment,” says Professor David Langlais, a genomicist at McGill University.
David studies how our epigenome regulates our immune system, including how it orchestrates the body’s response to infection and prevents inflammatory responses when they are not needed. Through a variety of laboratory techniques, he and his team are uncovering the precise mechanisms that control gene expression during immune responses.
Epigenetics and the immune system
Our immune system is responsible for protecting us against diseases. “Every day, our bone marrow produces billions of new immune cells,” says David. “These cells start as stem cells and develop into immune cells due to coordinated changes in the epigenome.” However, even when fully specialised, these cells can still change and adapt if pathogens are detected. “Fighting an infection involves immune cells changing their behaviour,” says David. “This, too, is controlled by the epigenome.”
The principal tools of gene expression are specialised proteins called transcription factors. “Transcription factors recognise and attach to a specific DNA sequence, triggering changes in the local epigenetic status and influencing the expression of genes,” says David. “The set of transcription factors in a cell determines what type of cell it is and what it can do.” But beyond these static sets of transcription factors that determine cell identity, there are also additional on-demand transcription factors that respond to environmental changes. “For example, Interferon Regulatory Factor 1 (IRF1) is an ‘emergency’ transcription factor produced only when immune cells need to activate against a threat,” says David. “Once activated, IRF1 finds its target sites in the genome, reshapes the epigenome, and switches on the genes that help the body fight off pathogens.”
Studying the epigenome
David’s lab uses a variety of cutting-edge genomic and single-cell multiomic techniques in cultured cells, animal models and human samples to study how transcription factors shape the epigenome of immune cells. “One technique uses antibodies engineered to recognise a specific transcription factor,” explains David. “This means we can pinpoint exactly where these transcription factors bind to the DNA inside a cell, allowing us to map their footprints across the genome and understand which genes are regulated by each transcription factor, and how.”
David uses single-cell studies to examine individual cells in great detail, rather than studying a whole tissue and getting average results from the thousands of cells that make up that tissue. “Single-cell multiomic techniques allow us to see, on a very detailed level, how the epigenetic changes influence gene activity,” explains David. “Studying individual immune cells is important because gene activation changes rapidly, and we want to know exactly which transcription factors are active in each activation state, and what goes wrong if they malfunction.”
By modifying or removing specific genes in mice, David’s animal model experiments allow him to study how certain transcription factors control immune responses in living organisms. “Mice share many similarities to humans, so our observations help us understand what happens during infections or autoimmune diseases in people,” he explains.
The third aspect of the lab’s research involves studying blood and tissue samples from human patients. “This is really important, because what happens in lab models doesn’t always perfectly match what happens in real people,” says David. “By comparing results from all our approaches, we can build a more complete and accurate picture of how immune cells work.”
From research to discovery
David and his team regularly collaborate with clinicians to uncover the genetic causes of severe immune problems in children. Often, they discover new mutations in genes or transcription factors that are disrupting the function of the immune system. “Recently, we identified IRF1 mutations in two infants that meant their immune systems couldn’t defend them against infections from common (and usually harmless) bacteria,” says David. His lab demonstrated that these mutations impaired the development of critical types of immune cells and inhibited the activation of others, leading to a very weak immune system.
David’s lab also studied the epigenetic causes of rheumatoid arthritis, a common autoimmune disease in which the immune system mistakenly attacks the cells lining the body’s joints. The team used single-cell multiomics to study cells from human patients and mice with rheumatoid arthritis and found that the stem cells that produce new immune cells had an altered epigenome, causing the new immune cells to be more inflammatory.
“Our research aims to uncover how transcription factors and the epigenome control immune responses, which has big implications for genomic medicine,” says David. “By identifying epigenetic changes linked to immune dysfunction, our work could help detect immune diseases earlier.” With a better understanding of transcription factors and epigenetic effects on the immune system, scientists will be able to create targeted therapies for infections and autoimmune diseases. “Ultimately, I hope our work bridges fundamental research and clinical applications, paving the way for new, more effective genomic-based treatments.”
Professor David Langlais, PhD
Inflammation Genomics Lab, Dahdaleh Institute of Genomic Medicine, Department of Human Genetics, Department of Microbiology and Immunology, McGill University, Canada
Fields of research: Genomics, immunology
Research project: Investigating how transcription factors and the epigenome impact the immune system
Funders: Canada Institute of Health Research (CIHR), Genome Canada, Genome Québec, Fonds de recherche Québec – Santé (FRQS), McGill Interdisciplinary Initiative in Infection and Immunity (MI4), Canada Foundation for Innovation (CFI), Richard and Edith Strauss Foundation
Website: langlaislab.com
Reference
https://doi.org/10.33424/FUTURUM580
About genomics
Genomics is the branch of molecular biology that studies the genome. “Genomics combines biology, technology and data science to solve real-world problems,” says David. “Whether you are interested in research, healthcare, biotechnology or AI, you can apply your interests in genomics.”
Genomics technology has become exponentially more powerful over the last few decades. Back in the 1990s and 2000s, the landmark Human Genome Project took over twelve years to sequence the first human genome; nowadays, the same task can be done in a matter of hours. “As sequencing technologies improve and become more affordable, we’re generating massive amounts of genomic and epigenomic data – but this brings its own challenges,” says David. “The next generation of genomicists faces the task of making sense of all these data.”
Genomics has now reached the stage where clinical applications become increasingly feasible. “Turning genomics knowledge into personalised therapies remains a big task,” says David. “My lab is relentlessly pushing in this direction with some promising developments.” These twin challenges of data interpretation and clinical application may be overcome with the help of another emerging technology – artificial intelligence. “Over the next decade, I expect major advances in AI-driven data analysis,” says David. “This will help us better understand how cells communicate, how diseases develop and how to design highly targeted, patient-specific treatments.”
Like many fields, genomics hinges on effective interdisciplinary collaboration. “In our lab, we bring together bioinformaticians, geneticists, immunologists and molecular biologists,” says David. Clinicians and patients have especially important roles in genomics research, as they provide valuable insights about how research is applied in the real world. “With the right tools and collaborations, the future of genomic medicine looks incredibly promising!” says David.
Pathway from school to genomics
At high school, biology, chemistry, mathematics and computing will introduce you to the foundational skills and knowledge needed for further study in the field of genomics.
“My best advice is to stay curious!” says David. “Read articles, watch documentaries and listen to science podcasts. Also, as genomics is becoming increasingly computational, learning basic programming and statistics will give you an edge.”
At university, a degree in genetics, molecular biology or computational biology could lead to a career in genomics. Some universities offer postgraduate degrees in genomic medicine, where you will learn how to apply genomic approaches to treat patients.
“One common mistake is overspecialising too soon,” warns David. “Don’t limit yourself and miss out on connections between different fields.” He emphasises the value of being able to both conduct genomic experiments and analyse data using bioinformatics, a skillset that is in high demand.
Explore careers in genomics
Careers in genomics include roles in academic research, healthcare, biotechnology and the pharmaceutical industry.
Organisations such as Your Genome (yourgenome.org), the Canadian Epigenetics, Environment and Health Research Consortium (thisisepigenetics.ca) and the National Human Genome Research Institute (genome.gov/About-Genomics/Educational-Resources) provide educational resources about genomics and epigenetics and profile the huge range of careers in the field.
Look for opportunities to gain practical experience while you are in high school, as hands-on learning is the best way to discover what excites you. Many university genomics labs offer lab tours, outreach programmes or summer internships, including those in McGill’s Institute of Genomic Medicine (genomic.medicine.mcgill.ca).
“Don’t be afraid to reach out to scientists,” advises David. “Many of us are happy to answer questions and help guide the next generation of genomic researchers. The field is growing quickly, and there’s a place for anyone passionate about discovery and innovation!”
Meet David
As a teenager, I wasn’t sure what career I wanted to pursue. That changed thanks to a high school assignment where we had to interview a professional. I reached out to a molecular geneticist and her passion for research was so inspiring that it sparked my interest in biomedical science. From that moment on, I knew I wanted to be part of the field.
I’ve been fortunate to have inspiring mentors throughout my training. The most influential was Professor Philippe Gros, a world-renowned geneticist who supervised my postdoctoral fellowship. His mentorship shaped and solidified my desire to pursue academic research, particularly in genomics and immunity, which eventually led me to establish my own research lab.
Now, I enjoy mentoring students myself. I love helping them develop their skills, think critically and get excited about research while making discoveries together. I also love the freedom to explore scientific questions that could make a real impact on people’s lives.
One of my favourite facts is that our immune system has memory at the epigenetic level. We often think of adaptive immune cells remembering past infections to respond better next time, but recent research, including our own, has shown that even innate immune cells can ‘remember’ through epigenetic reprogramming. This discovery could lead to new ways to boost immune defences or regulate excessive inflammation in autoimmune diseases like rheumatoid arthritis.
In my free time, I love spending time with my family. My three boys, my wife and I are obsessed with downhill skiing – whether it’s racing down the slopes or just enjoying the mountains together, skiing is a big part of our lives during the cold winter months in Canada.
David’s top tips
1. Be resilient and embrace challenges. Research is full of setbacks, but each is an opportunity to learn. Don’t be discouraged by failure.
2. Enjoy the journey! Science is about discovery, and there’s always something new to learn!
Meet Mathieu
Dr Mathieu Mancini is a Postdoctoral Fellow in David’s Lab.
As a teenager, I enjoyed participating in school theatre productions. I also played the piano and oboe, and I spent a lot of time trying to play the soundtracks to my favourite movies and video games!
I was inspired to become a genomics researcher by friends at university who were passionate about using new coding and programming tools, but who also knew the value of lab work for conducting experiments. Today, I am inspired every time I see how our expertise in genomics can make a positive difference in a new student’s journey, or for our clinician partners who learn from our work and improve their patients’ treatments.
I am very lucky to work with cutting-edge sequencing methods. I can analyse and measure things that nobody has seen before. I love spotting patterns in my data, comparing my work to other research, and bringing it all together in a clear and succinct message.
My days typically start with a coffee and chat with my colleagues. I usually prioritise ‘wet lab’ bench experiments, then while I’m waiting for them to finish, I return to my computer to check on my bioinformatics analyses. If I receive a call from our clinician partners about new patient samples then I’ll clear my schedule and focus on processing them for sequencing.
When I first learned that medical doctors who study inflammatory diseases are called rheumatologists, I was surprised! ‘Inflammation’ comes from a word meaning ‘to catch fire’, but ‘rheumatology’ comes from a word meaning ‘flowing current’, like a stream. Just like the immune system, the words we use to describe it are full of contrasts!
At the end of the day, I enjoy taking time to cook a good meal. In my free time, I play the piano and enjoy reading.
Mathieu’s top tip
Read widely and keep your interests broad. Thinking differently or creatively, or collaborating with colleagues with diverse backgrounds, can often help you move forward in scientific work and keep things interesting and meaningful.
Do you have a question for David?
Write it in the comments box below and David will get back to you. (Remember, researchers are very busy people, so you may have to wait a few days.)
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