Monarchies and Hierarchies in Shaping Chromatin Landscapes

Over the past decade the Viennese JakStat Consortium has established itself as one of the leading groups worldwide in the study of signal transmission by the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). JAKs and STATs signal through many different receptors into the nuclear chromatin and reprogramme cellular function by changing gene expression. The generation and analysis of advanced transgenic mouse models for human disorders, such as haematopoietic malignancies and infectious diseases, has enabled the Consortium to contribute substantially to our understanding of the functions of JAKs and STATs. The results from Vienna and elsewhere have led to the recognition of the JAK-STAT pathway as one of the twelve core pathways in the initiation and progression of cancer and as one of the key pathways in the defence against infection. Despite recent progress, our knowledge of JAK-STAT biology is essentially one- dimensional: the mechanisms of signal integration and the changes to chromatin architecture driven by JAKs and STATs under healthy and diseased conditions are only starting to emerge. The architecture or landscape of chromatin - a higher order complex of DNA, proteins and RNA - critically determines the accessibility of genes to regulatory proteins. JAK-STAT signalling components are known to interact with chromatin remodelling proteins. Chromatin modifiers and JAKs or STATs are dysregulated, i.e. mutated, hyperactivated or lost, in many different cancers. The chromatin landscape changes when immune cells differentiate to exert specialized functions, e.g. recognition and elimination of pathogens. This creates a unique and complex disease genome/chromatin. Our mission is to discover how the mutated or differentially activated proteins interact to form and drive cancer and immune responses. In particular, the monarchs at the top of the hierarchy of chromatin remodelling and gene regulation need to be determined. Understanding the dynamics and reconfiguration of chromatin will allow us to compare human diseases with models in genetically engineered mice, in which we can test new therapeutic concepts. The work meets ethical standards and 3R principles with respect to analysing patient samples and animal experimentation. Our interdisciplinary network is based on next-generation whole genome and proteome technologies with a strong bioinformatics core competence. Seven internationally competitive groups from the University of Vienna (Thomas Decker), the Medical University of Vienna (Sylvia Knapp), the Ludwig Boltzmann Society (Richard Moriggl) and the Research Center for Molecular Medicine of the Austrian Academy of Sciences (Christoph Bock) under the guidance of the University of Veterinary Medicine (Richard Moriggl, Mathias Müller, Veronika Sexl, Birgit Strobl) and with expertise in bioinformatics, epigenetics, immunology, infection medicine, transgenetics, oncology, molecular pharmacology and translational medicine are joining forces with the vision of developing the era of precision medicine. Networking will allow optimal use of infrastructure and create synergy.

For over a decade, the Consortium has been funded as a Special Research Program (SFB) by the Austrian Science Fund (FWF). It has made substantial contributions to the current understanding of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) as central regulators of homeostasis and disease. The JAK-STAT pathway is a communication node for the immune system and recognised as one of the twelve core pathways in the initiation and progression of cancer and chronic inflammation. The JAK-STAT consortium's progress has been fuelled largely by the generation and analysis of advanced transgenic mouse models for a number of human disorders, such as haematopoietic malignancies as well as infectious, inflammatory, and metabolic diseases. Next-generation sequencing and proteome technologies based on strong bioinformatics competence were deployed to advance the knowledge of chromatin architectures that govern (patho)-physiological processes. The integrative efforts of all SFB members have produced the comprehensive transcriptome and chromatin accessibility profiles of splenic immune cells isolated from 12 JAK-STAT genetically engineered mouse lines. The dataset implies that JAK-STAT signals can not be seen as binary on-off switches but maintain baseline activity in their in vivo tissue context, with widespread epigenetic and transcriptional implications that help maintain the cells' regulatory state of readiness and their ability to respond rapidly to challenge. JAK and STAT inhibitors are in development or already in clinical use for the treatment of various cancers and hyper-inflammatory conditions. The results of our consortium contribute to the understanding of the molecular actions, treatment efficacies and side effects of these pharmaceuticals.