Get to know Jörg Tost, epigenomics researcher
Over the last decade or so, there has been incredible growth in the field of epigenomics.
Technological advancements, especially in methylation detection methods such as Pyrosequencing, whole genome bisulfite sequencing and targeted approaches, have allowed this field to blossom. As this area of research has expanded, it has become increasingly clear that methylation status across the genome is a crucial regulator of normal biological processes. In addition, modifications to methylation patterns are intimately linked to disease. Indeed, many cancers are associated with increased methylation of CpG islands and subsequent silencing of tumor-suppressor genes. Epigenetic alterations are associated with other complex diseases as well, such as diabetes and allergic disorders.
To get a better handle on the past, present and future of epigenomics research and its implications for medicine, we sat down with Dr. Jörg Tost, an expert in methylation detection technology. Dr. Tost is Director of the Laboratory for Epigenetics and Environment at the Centre National de Recherche en Génomique Humaine, CEA, Institut de biologie François Jacob, Université Paris-Saclay.
To learn more about the technology and approaches used in Dr. Tost’s lab, check out his on-demand webinar here!
Photograph of Dr. Tost and his lab, copyright F. Rhodes – CEA.
1. Tell me a little about your background. What motivated you to pursue a career in epigenetics research?
After studying chemistry in my undergraduate years, I came into contact with epigenetics and, more specifically, DNA methylation analysis from a technological angle in my Ph.D. thesis. We developed new assays for quantitatively measuring DNA methylation, first using MALDI mass spectrometry and later based on Pyrosequencing, a technology for which we have been widely known. At that time, epigenetic analysis was still an emerging discipline performed in a limited number of laboratories. Genome-wide association studies based on frequent genetic variants were thought to provide important clues for our understanding of complex human diseases, but these hopes were not fully met. Epigenetic modifications are an attractive alternative for explaining disease susceptibility and providing cues for differential disease courses.
I have always been fascinated by the epigenome, which constitutes the record of our cells’ responses to environmental exposure, encompassing both the outside environment, such as where we live and our lifestyle, but also the internal environment, such as hormones or signals from surrounding cells. The epigenome is multilayered with several levels of molecular modifications interacting in a complex gene regulatory network and there is rarely a definite “yes or no” answer. Changes are subtle and, in many cases, reversible, but at some point, events might push the epigenome out of its balanced state, which might be associated with changes in phenotype or disease states. Early life environmental influences might play a key role in the adaptive capacities of our epigenome and how we will later be able to cope with different stimuli.
We have greatly increased our knowledge of epigenetics in the twenty years I have been in the field, and epigenetic changes have been implicated in most complex human diseases and altered by many environmental exposures. However, we are only starting to grasp its scope and how we might use this for individualized patient management or use alteration of the epigenome as a target for therapeutic intervention or one day even prevention. Much remains to be explored, there will be many surprises and I doubt that I will ever get bored of exploring epigenetics in my career.
2. You recently presented your work at a symposium at the Advances in Genome Biology and Technology 2021 Meeting (AGBT). You mentioned a new, NGS-based targeted approach for detecting methylation status in samples – QIAseq Targeted Methyl Custom Panels. What did you want attendees to learn and take away from your presentation on this technology?
We are very excited about this new multiplex amplicon assay, and we had the chance to closely collaborate with QIAGEN to make the technology robust and mature. This approach allows us to analyze thousands of CpG positions of interest in large cohorts of samples simultaneously. It really complements the other technologies we have set up for either comprehensive genome-wide analysis of DNA methylation patterns using microarrays or next-generation sequencing and the high-resolution quantitative analysis of specific loci of interest.
We find the method using targeted custom panels very attractive, particularly as it allows you to choose the CpGs of interest for a given project. Panels can be easily updated by adding additional primers or removing CpGs that have not been validated. These panels are also robust, meaning they are amenable to high-throughput analysis when using automation, and they require only standard genomics laboratory equipment – no need for special instrumentation or techniques. In addition, the use of Unique Molecular Indices allows us to quantitatively determine DNA methylation levels – even with a limited amount of starting material. We think that the assay will provide a very useful tool when translating results from genome-wide studies to more targeted validation steps that don’t rely on the presence of probes on microarrays.
3. Why do you think epigenetics has become such a popular area of study over the last several years?
Epigenetics has been omnipresent over the last decade, and epigenetics and epigenomics have experienced a lot of hype. Epigenetics was regarded as a solution for resolving the problem of missing heritability, which came from the disappointing realization that large-scale genetic studies, particularly genome-wide association studies, did not fulfill the initial promise of explaining complex diseases. Rare variants and structural variation might account for some of this missing heritability. Epigenetics, however, allows us to measure the effects of the environment on our genome, which, in combination with our DNA sequence, determines phenotype and disease susceptibility. We have learned in the past decade that epigenetic changes are present in most complex diseases and not only cancer. Epigenetic changes often precede clinical manifestations. As a DNA-based marker, DNA methylation is technically very attractive to be implemented as a biomarker for multiple clinical applications, including screening of at-risk populations, diagnostics and monitoring of treatment response or resistance. Epigenetic analyses in liquid biopsy provide an attractive non-invasive means for diagnostics or monitoring disease recurrence. When disease-relevant cells die and release DNA with their cell-type-specific epigenetic markers into blood, these potentially disease-associated changes can be detected, along with their tissue of origin. While this technique was pioneered in cancer research, applications have diversified and now include transplantation rejection, traumatic brain injury and detection of diabetes. In fact, DNA methylation-based biomarkers have been approved by regulatory agencies for screening at-risk patients for certain types of cancer, paving the way to new types of biomarkers.
We have also learned that at least some types of environmental exposure, such as smoking, lead to highly reproducible and long-lasting epigenetic changes. Therefore, the epigenome seems to provide a record of what a person has been exposed to over their lifetime and might, in combination with the DNA sequence, explain the onset and course of certain diseases with greater clarity.
Another fascinating discovery has been the differential epigenetic activation state of certain cells. For example, some vaccines have been shown to induce epigenetic alterations in innate immune cells, which, unlike adaptive immune cells, are thought to have no memory. However, this memory-like effect results in increased responsiveness in cases of a second unrelated infection. There are so many facets to epigenetics that it will take a long time to understand them better.
4. How do you think the field will evolve over the next decade? What major advances do you expect (or hope) to see?
New knowledge is often driven by technological advances. There is currently a lot of development in the space of single-cell epigenomics. Further improvement of these technologies is required, but this would circumvent some of the problems inherent to epigenetic analysis. Furthermore, it would allow us to better assess the different epigenetic activation states in a defined population.
Application of spatial transcriptomics, which allows the measurement of gene expression patterns of cells in their microenvironment, would also be of great interest for the analysis of epigenetic modifications. We have learned in the last decade that epigenetic changes are present in many complex human diseases, not only cancer. In many cases, there is no strong genetic variant driving these diseases. There is a huge potential for epigenetics to contribute to personalized patient management with respect to these diseases enable early detection, predict which treatment might be best suited for a patient and monitor the success of treatment or development of treatment resistance. To be fully appraised and clinically implemented, it will be important to include epigenetic analysis in clinical trials on a routine basis. The challenge comes from the cell type specificity of DNA methylation and epigenetic modifications in general, which will require isolation of specific cell types. This is associated with a substantial logistical effort, but might lead to completely novel insights and perhaps new targets for therapy.
Epigenetic tests might, in the near future, also allow us to better measure and monitor the exposure of individuals to substances that are potentially harmful to human health. On the other hand, we might get a scientifically-supported handle to keep the epigenome in a healthy state. Interventions like these, like modifying the microbiome, have attracted some interest, but the interactions between the microbiome and epigenome are still poorly understood.
5. In one of your recent review articles, you mention the future prospect of “epigenetic editing”, analogous to genetic editing using CRISPR/Cas9. How far away do you think we are from medical interventions using epigenetic modification techniques? What will it take to get to that point?
Epigenetic editing is an intriguing recent development in the field of epigenetics. It allows us for the first time to specifically alter the epigenomic landscape at specific loci and interrogate the functional relevance of epigenetic changes in a biomedical context, such as a disease. For the moment, epigenetic editing is mainly used for in vitro experiments aimed at reproducing an epigenetic state associated with a phenotype, although some experiments have been performed in animal models. Clinical applications, especially in diseases without strong genetic drivers, might be possible in the future. However, there are still many open questions for application to complex organisms such as humans with their multiple cell types. Delivery methods, efficiency of the editing steps, stability of the induced changes and the reaction of the cellular microenvironment are among the many challenges. In non-lethal diseases – or diseases for which other treatment regimens already exist – the risks and benefits need to be carefully balanced. These tasks are indeed complex as the redundant multi-layered epigenomic landscape will require a well-planned and rational approach to identify the “Achilles’ Heel” of the epigenome and avoid compensatory mechanisms for obtaining measurable and durable results. Much work on the hierarchy of epigenetic modifications and improved strategies are required before epigenetic editing might enter clinical routine, but the progress in this field has so far been breathtakingly rapid.