25.01.2021: The Special Research Programme (SFB) “Monarchies and Hierarchies in Shaping Chromatin Landscapes”, coordinated by the University of Veterinary Medicine Vienna, has been extended for four years. The decision to award further funding was taken at the Austrian Science Fund’s final board meeting of 2020. The extension will allow the research group led by Mathias Müller at Vetmeduni, to continue down its successful path of recent years. The group aims to gain further insights into the role of the JAK-STAT signalling pathway in the development and treatment of infection, inflammation and cancer.
The SFB research platform is bringing together the activities of a network of researchers at a number of universities and institutes. Participants benefit significantly from common standards and protocols and from the close collaboration of experts in molecular genetics, epigenetics, tumour genetics, pharmacology, bioinformatics and intensive care medicine, which is unique in the world.
The researchers are investigating the JAK-STAT signalling pathway and its influence on organ-specific and tissue-specific chromatin activities characteristic of the development and resolution of infection, inflammation and cancer. The research at Vetmeduni´s Institute of Animal Breeding and Genetics is focused on TYK2 and STAT1 in the spleen (Mathias Müller and Birgit Strobl) and on oncogenic STAT5 in T-cell forms of leukaemia (Heidi Neubauer and Richard Moriggl). Work on the oncogenic cooperation of CDK6 with STAT3 and STAT5 (Veronika Sexl and Barbara Maurer) is being undertaken at the Institute of Pharmacology and Toxicology of the University of Veterinary Medicine Vienna and additional participants include the Max Perutz Labs at the University of Vienna (Thomas Decker and Matthias Farlik), the Medical University of Vienna (Sylvia Knapp) and the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (Christoph Bock and Thomas Krausgruber).
Focus on chromatin
Chromatin is a tightly packed complex of DNA, protein and RNA with a three-dimensional structure (“landscape”) that has a key role in regulating gene expression and cell function. Chromatin remodelling, the dynamic modification of the chromatin architecture, is regulated by biochemical changes to the chromatin and to the proteins that can read, insert and delete the modifications. The mechanisms form the basis of epigenetics.
JAKs (Janus kinases) and STATs (signal transducers and activators of transcription) transmit signals from the cell surface to the nucleus, where they influence cell function by modifying chromatin structure and regulating gene expression. JAKs or STATs are deregulated in many forms of cancer as well as in immunological or inflammatory diseases, for example through over-activation, loss of function or genetic alteration. This creates a unique and complex “disease genome/chromatin”.
Hierarchies and monarchies unclear
For several years, the research coordinated at Vetmeduni Vienna has studied these differentially activated or mutated proteins to understand how they interact with one another to cause disease. The chromatin landscape also changes during cell differentiation and specialization, e.g. during the recognition and elimination of pathogens or cancer cells or during inflammation. Epigenetic mechanisms are responsible for cell memory and for the regulation of physiological functions (homeostasis). All these processes are influenced by JAK-STAT signalling, although how the various signals are interconnected it is unclear. In particular, we have not yet clarified the hierarchy of the regulatory proteins nor have we identified the key protein (“monarch”) in the restructuring of chromatin or in gene regulation.
Research enables new therapeutic approaches
The consortium is aiming to characterize the chromatin landscapes of various cell types and to understand how they are modified by JAKs and STATs in healthy and diseased states. Understanding chromatin dynamics and remodelling will make it possible to compare infectious and inflammatory diseases and leukaemias in humans using genetically modified mice and to test new therapeutic concepts.
All research complies with ethical guidelines and the 3R principles for analysing patient samples and experimenting with animals. The interdisciplinary network is based on next-generation whole genome and proteome technologies with a strong competency in bioinformatics. Seven internationally leading research groups with expertise in epigenetics, immunology, infection medicine, transgenetics, oncology, molecular pharmacology and translational medicine have joined forces with the vision of advancing the era of personalized/precision medicine and comparative medicine. The high degree of networking opportunities and many years of successful cooperation between the partners ensure that they can make optimal use of the available infrastructure while guaranteeing synergies in the work.
The Special Research Programme was established in 2006 and is therefore the “oldest” Special Research Programme in the life sciences in Austria. Detailed information can be found at www.jak-stat.at.