Footprints on the genome – how immune cells orchestrate their functions
RCI and UKR scientists identified the transcription factor EGR2 as a major orchestrator of DNA methylation landscapes in human blood monocytes.
All cells in our body contain the entire genomic information that is necessary for the organism to survive. Because each single cell fulfills specific tasks in the body, it uses only parts of this information to execute its function. The selection of genes that a specific cell uses is regulated by “epigenetic” mechanisms. They operate to control and memorize the identities and functions of all the different cell types of our body. Epigenetic mechanisms are essential for life and frequently altered in human diseases, including cancer. Understanding how these mechanisms work in normal cells is important to better comprehend their contribution to human disease and to develop targeted therapies.
A particular epigenetic mark – called DNA methylation- involves a chemical modification of our genetic material and is responsible for silencing gene expression. Therefore, the DNA methylation patterns of the genome determine the function of a cell. But how cells define their individual methylation patterns is not yet understood. Scientists of the Regensburg Center for Interventional Immunology (RCI) together with researchers from the University Hospital Regensburg (UKR) have now identified the transcription factor EGR2 as a major orchestrator of DNA methylation landscapes in human blood monocytes. Monocytes are a particularly fundamental type of immune cells which orchestrate many important processes within the body, such as the primary response to infections or wound healing. They found that EGR2 is critical to activate regulatory elements in methylated DNA, which makes EGR2 a major epigenetic “pioneer factor” in monocytes. The pioneer factor EGR2 promotes gene activation by recruiting the protein complexes that remove the methylation mark from the DNA thereby determining monocyte function. These findings are now published in the journal Nature Communications.
The group of RCI and UKR researchers, led by Michael Rehli, PhD, compared the distribution of DNA methylation across the entire genome between human blood monocytes and dendritic cells – a monocyte-derived, functionally specialized cell type – and identified thousands of regions in the genome that lose DNA methylation during the transition from one cell type into the other. These genomic regions were enriched for sequences of our genetic code that are typically recognized by a particular group of proteins, called transcription factors, which regulate gene expression. Using a variety of approaches, the authors further characterized candidate transcription factors for their ability to alter DNA methylation patterns. These analyses revealed an essential role for EGR2 as “pioneer factor” in human monocytes. “We show that DNA methylation “footprints” of this pioneer factor are detectable before we can see the factor itself, suggesting that transient visits of the factor are sufficient to trigger epigenetic changes.” said Karina Mendes, PhD, first author of the study.
“We are addressing a classical chicken and egg question in epigenetics. What’s first – transcription factor binding or epigenetic modification? Does the transcription factor require the epigenetic modification, or does it recruit the modifier? Here we provide evidence that pioneer factor-driven epigenetic changes can occur in the absence of stable protein binding to the DNA.” noted Michael Rehli, the senior author of the study.
Understanding how epigenetic landscapes in monocytes are shaped may enable us to manipulate them and eventually help to make monocytes more effective in fighting cancer. The authors are therefore currently investigating the consequences of DNA methylation changes in human monocytes to pinpoint the mechanisms through which EGR2 exerts its functions. They are also planning to assess whether similar DNA methylation footprints in cancer cells are associated with cancer-specific pioneer factor activity.
About the RCI
The RCI Regensburg Center for Interventional Immunology, an extra-university research center, focuses on translational immunology in the fields of cancer immunotherapy, chronic inflammation and autoimmunity. Its objective is to develop effective cellular immunotherapies in these areas.
About the UKR
The University Hospital Regensburg is the only maximum care provider in Eastern Bavaria with a special focus on high-performance medicine, particularly in the areas of transplantation and intensive care medicine as well as oncological and cardiovascular diseases. In terms of average case severity („case mix index“), the UKR is at the top of German university hospitals.
Michael Rehli, PhD
Mendes K, Schmidhofer S, Minderjahn J, Glatz D, Kiesewetter C, Raithel J, Wimmer J, Gebhard C, Rehli M. The epigenetic pioneer EGR2 initiates DNA demethylation in differentiating monocytes at both stable and transient binding sites.Nat Commun 12, 1556 (2021).