News

Innate immunity to viral infection is achieved by a group of polypeptide mediators, the interferons (IFN). By binding to cell surface receptors they initiate signal transduction via Janus kinases (JAK) that the STATs target, a group of transcription factors. STATs combine to form a transcription factor, ISGF3, that activates transcription of a large number of IFN-induced genes (ISG) encoding antiviral proteins and establishing an antiviral state.
We show that the transcription of antiviral genes includes important changes of chromatin structure (see below). First, ISGF3 binds to the control region of ISG to induce a rearrangement of nucleosomes that creates maximal accessibility of the promoter (below middle panel). Second, ISG that are arranged in chromosomal clusters change their chromatin loop structure to increase the interaction of regulatory elements (below right panel). The molecular model emerging from the study posits that interaction in the 3-dimensional space creates regulatory hubs with the ability to influence the expression of several clustered genes simultaneously. This may help to both coordinate, accelerate and strengthen the establishment of the antiviral state.

IFN stimulus alters the 3-dimensional chromatin architecture at antiviral gene clusters

Published in iScience

Ekaterini Platanitis, Sthephan Gruener, Aarathy Ravi Sundar Jose Geetha, Laura Boccuni, Alexander Vogt, Maria Novatchkova, Andreas Sommer, Iros Barozzi, Mathias Müller, Thomas Decker

Interferons reshape the 3D conformation and accessibility of macrophage chromatin

https://doi.org/10.1016/j.isci.2022.103840

Our work builds on a previously published paper (https://doi.org/10.1038/leu.2016.277) describing germ-line TYK2 gain-of-function (GOF) mutations identified in childhood leukemia. In close collaboration with the Dutch pediatric oncologists we studied the oncogenic and druggable properties of the two activating mutations of this JAK family member tyrosine kinase. We demonstrate the transformation capacity of the potent TYK2^P760L mutation in various hematopoietic cell systems and its tumorigenic potential upon transplantation into mouse models. The highly selective TYK2 inhibitor deucravacitinib blocked GOF TYK2 activity. A screen for kinase pathways co-operating with oncogenic TYK2 identified the PI3K/AKT/mTOR and CDK4/6 pathways as top hits. Combinatorial treatment of the TYK2inib with blockers of these pathways turned out to be more efficacious than single treatments and could be successfully translated to PDX cells derived from the TYK2^P760L mutation carrying patient. The original work with contributions from the SFB members Birgit Strobl, Veronika Sexl, Richard Moriggl and Mathias Müller establishes novel treatment options for acute leukemia in patients harboring GOF TYK2 mutations and has not been submitted to publication elsewhere.

Published in Haematologica

Katharina Wöss, Sabine Macho-Maschler, Dorette S. Van Ingen Schenau, Miriam Butler, Caroline Lassnig, Daniel Valcanover, Andrea Poelzl, Katrin Meissl, Barbara Maurer, Tania Brandstoetter, Claus Vogl, Anna Koren, Stefan Kubicek, Anna Orlova, Richard Moriggl, Birgit Strobl, Veronika Sexl, Frank N Van Leeuwen, Roland P Kuiper, Mathias Müller

Oncogenic TYK2^P760L kinase is effectively targeted by combinatorial TYK2, mTOR and CDK4/6 kinase blockade

https://doi.org/10.3324/haematol.2021.279848 

Vetmeduni Vienna, January 25th 2021:

Extension of “Monarchies and Hierarchies in Shaping Chromatin Landscapes” Special Research Programme funded by Austrian Science Fund FWF

https://www.vetmeduni.ac.at/en/infoservice/press-releases/presseinformationen-2021/extension-of-monarchies-and-hierarchies-in-shaping-chromatin-landscapes-special-research-programme/

Second funding period (2021-2025) for SFB F61 approved in the FWF Board meeting from 23^rd to 25^th of November 2020.

Summary of the Research Program

The STAT proteins are transcription factors with a central role in cell homeostasis, survival and differentiation. They are activated by the JAK kinases, including TYK2. Dysregulated STATs cause immune- or inflammation-related, metabolic and tumorigenic diseases but how STATs interact with chromatin is unknown. We have compiled a map of chromatin activity for all wildtype STATs, TYK2, oncogenic STAT5B and a kinase-inactive TYK2 mutant in primary immune cells and in structural cells under homeostatic, cytokine-induced and cell-transforming conditions and plan to use it to determine how JAK-STAT exerts its manifold effects.

The SFB groups hypothesise

• STATs and TYK2 cause chromatin remodeling in non-hematopoietic cells, defining their identity and shaping the interface of immune cells and stromal cells in homeostasis and disease (Christoph Bock, Mathias Müller, Birgit Strobl with all other consortium members)
• Homeostatic macrophages use STAT2/IRF9 to prime themselves for activation (Thomas Decker, Sylvia Knapp and Christoph Bock); signals from STAT1,3,5 drive the exit from and the return to homeostasis (Sylvia Knapp, Mathias Müller, Birgit Strobl, Thomas Decker and Christoph Bock)
• STAT5A and STAT5B are not equivalent but drive distinct developmental programs in haematopoietic and leukaemic cells (Veronika Sexl, Heidi Neubauer and Christoph Bock)
• The chromatin signatures of haematopoietic cancers are shaped by oncogenic STAT5, oncogenic STAT3 or a STAT3-CDK6 complex (Veronika Sexl, Heidi Neubauer and Christoph Bock)
• TYK2 determines cell fate by regulating both transcriptional and post-transcriptional processes (Birgit Strobl, Mathias Müller and Christoph Bock with Thomas Decker).

Much of the current work on signal transduction in disease conditions (e.g. during infection, transformation or drug treatment) is based on an outdated understanding of the homeostatic healthy condition. By providing a fine-scale and cell-specific definition, our work will cause a comprehensive (re-)evaluation of the early stages of perturbations and the return to homeostasis. The approach is completely novel and will revolutionize our understanding of cellular memory and the progression/resolution of disease.

In Q2 2021 a common seminar series of the FWF-funded Vienna Life Science Region research consortia of DocFund TissueHome (speakers Karl Kuchler & Birgit Strobl; https://tissuehome.meduniwien.ac.at), SFB HIT: HADCs – Immunomolulation – T cells (speaker Willfried Ellmeier; https://www-new.meduniwien.ac.at/HIT/) and the SFB JAK-STAT & Chromatin Landscapes (speakers Mathias Müller & Thomas Decker) will start. Please look out for the upcoming announcements.

Joined forces of FWF SFB with DFG TRR:

the Viennese JAK-STAT consortium and the DFG funded Transregio (TRR) research consortium ‘Determinants and Dynamics of Elimination versus Persistence of Hepatitis Virus Infection’ (TRR179) coordinated by Ralf Bartenschlager (http://www.trr179.de/en/) initiated a collaboration with future researcher exchanges and lab visitations.

Vetmeduni Vienna, January 25th 2021:

Extension of “Monarchies and Hierarchies in Shaping Chromatin Landscapes” Special Research Programme funded by Austrian Science Fund FWF

https://www.vetmeduni.ac.at/en/infoservice/press-releases/presseinformationen-2021/extension-of-monarchies-and-hierarchies-in-shaping-chromatin-landscapes-special-research-programme/

Second funding period (2021-2025) for SFB F61 approved in the FWF Board meeting from 23rd to 25th of November 2020.

Summary of the Research Program

The STAT proteins are transcription factors with a central role in cell homeostasis, survival and differentiation. They are activated by the JAK kinases, including TYK2. Dysregulated STATs cause immune- or inflammation-related, metabolic and tumorigenic diseases but how STATs interact with chromatin is unknown. We have compiled a map of chromatin activity for all wildtype STATs, TYK2, oncogenic STAT5B and a kinase-inactive TYK2 mutant in primary immune cells and in structural cells under homeostatic, cytokine-induced and cell-transforming conditions and plan to use it to determine how JAK-STAT exerts its manifold effects.
The SFB groups hypothesise
• STATs and TYK2 cause chromatin remodeling in non-hematopoietic cells, defining their identity and shaping the interface of immune cells and stromal cells in homeostasis and disease (Christoph Bock, Mathias Müller, Birgit Strobl with all other consortium members)
• Homeostatic macrophages use STAT2/IRF9 to prime themselves for activation (Thomas Decker, Sylvia Knapp and Christoph Bock); signals from STAT1,3,5 drive the exit from and the return to homeostasis (Sylvia Knapp, Mathias Müller, Birgit Strobl, Thomas Decker and Christoph Bock)
• STAT5A and STAT5B are not equivalent but drive distinct developmental programs in haematopoietic and leukaemic cells (Veronika Sexl, Heidi Neubauer and Christoph Bock)
• The chromatin signatures of haematopoietic cancers are shaped by oncogenic STAT5, oncogenic STAT3 or a STAT3-CDK6 complex (Veronika Sexl, Heidi Neubauer and Christoph Bock)
• TYK2 determines cell fate by regulating both transcriptional and post-transcriptional processes (Birgit Strobl, Mathias Müller and Christoph Bock with Thomas Decker).

Much of the current work on signal transduction in disease conditions (e.g. during infection, transformation or drug treatment) is based on an outdated understanding of the homeostatic healthy condition. By providing a fine-scale and cell-specific definition, our work will cause a comprehensive (re-)evaluation of the early stages of perturbations and the return to homeostasis. The approach is completely novel and will revolutionize our understanding of cellular memory and the progression/resolution of disease.

Acute myeloid leukemia (AML) is an aggressive form of blood cancer that affects children and adults. In cases with particularly poor prognosis, this cancer is triggered by oncogenic fusion proteins, the formation of which involves the Nucleoporin 98 (NUP98) gene. A study published in the journal Blood results from a collaborative effort, including the groups of Richard Moriggl and Veronika Sexl of the Vetmeduni Vienna, and introduces a new therapeutic approach to fight this disease.

Genetic rearrangements, in which the NUP98 gene is involved, are rare genetic events that occur repeatedly in AML patients and are associated with a particularly poor prognosis - especially if this process occurs in children and adolescents. In a cooperation that included the Institute of Biochemistry and the Institute of Pharmacology at the Vetmeduni Vienna, researchers have for the first time identified the genes that are activated directly by NUP98 fusion proteins.

The authors developed novel mouse models that mimic the rare blood cancer AML, which included NUP98-fusion proteins. By integrating chromatin occupancy profiles of NUP98-fusion proteins with transcriptome profiling they discovered that NUP98-fusion proteins directly regulate leukemia-associated gene expression programs. Among these is the CDK6 protein, for which molecular inhibitors were already approved for clinical usage to treat other types of cancer. The authors then showed that treatment with CDK6 inhibitors significantly improved the survival of the test animals. Further clinical studies are now required to confirm the effectiveness of targeted CDK6 inhibition in patients suffering from AML.

Johannes Schmöllerl, Inês Amorim Monteiro Barbosa, Thomas Eder, Tania Brandstoetter, Luisa Schmidt, Barbara Maurer, Selina Troester, Ha Thi Thanh Pham, Mohanty Sagarajit, Jessica Ebner, Gabriele Manhart, Ezgi Aslan, Stefan Terlecki-Zaniewicz, Christa Van der Veen, Gregor Hoermann, Nicolas Duployez, Arnaud Petit, Helene Lapillonne, Alexandre Puissant, Raphael Itzykson, Richard Moriggl, Michael Heuser, Roland Meisel, Peter Valent, Veronika Sexl, Johannes Zuber and Florian Grebien

Doi: https://doi.org/10.1182/blood.2019003267

The Science Fund FWF supports promising research projects with a total volume of 8.6 million euros, in collaboration with the Austrian Academy of Sciences (ÖAW). This is intended to promote the innovative and interdisciplinary collaboration of outstanding postdoc teams from Austrian universities. One of the approved "Zukunftskollegs" will be carried out by member of the Vetmeduni Vienna in the field of preclinical development of peptide therapeutics for the treatment of autoimmune and inflammatory diseases. The aim is to establish a platform for interdisciplinary drug development and to make drug candidates available for further clinical development.

The "PeptAIDes drug development" (Peptides for the treatment of Autoimmune and Inflammatory Diseases) is one of four approved projects and will be developed by Dagmar Gotthardt (from Veronika Sexl’s group) together with Roland Hellinger (MedUni Vienna), who is responsible for the coordination of the project, Tim Hendrikx (MedUni Vienna), Eva-Maria Zangerl-Plessl and Kirtikumar Jadhav (University of Vienna). “We are proud that one of our young scientists was selected in such an extremely competitive environment with such high demands” said Otto Doblhoff-Dier, Vice Rector for Research and International Relations at the Vetmeduni Vienna. The research platform "PeptAIDes" encompasses the entire range of the scientific disciplines involved in drug development. The aim of the project is to test peptides in preclinical studies for a future use in clinical trial stages.

New findings from researchers at the Department for Functional Cancer Genomics at the Vetmeduni Vienna, in cooperation with the Technical University of Denmark (DTU), provide insights into mechanisms of immune cells that could affect future therapies for human diseases. The study called “The neonatal microenvironment programs innate γδ T cells through the transcription factor STAT5“ includes the participation of member of Richard Moriggl’s group.

Our immune system contains specialized cells that act as the first answer against pathogens such as bacteria and viruses. These cells are called gamma-delta (γδ) T cells and are mainly found in organs such as the intestine, lungs, skin and lymph nodes. However, this specific T cells can also promote autoimmune and immune-related diseases such as psoriasis and multiple sclerosis. Understanding the basic biology of γδ T cells is essential in order to find ways to treat these diseases. In addition, by controlling the γδ T cells in a targeted manner, one could envision the use of these cells to fight infections and inflammations. This new study shows, for example, that STAT5 is necessary for the growth of certain types of γδ T cells during neonatal mouse life. Mice that do not express STAT5 do not produce these T cells and are resistant to multiple sclerosis. Furthermore, the authors describe a new type of γδ T cells that can only be found in the intestine. This new cell type has different functions than other types of γδ T cells and requires STAT5 for its growth. The results imply that the newly identified cell type is an important defence mechanism against intestinal infections shortly after birth.  Therefore, manipulation of γδ T cells may help to strengthen immunity in early age.

Published in The Journal of Clinical Investigation

Darshana Kadekar, Rasmus Agerholm, John Rizk, Heidi A. Neubauer, Tobias Suske, Barbara Maurer, Monica Torrellas Viñals, Elena M. Comelli, Amel Taibi, Richard Moriggl, and Vasileios Bekiaris

Doi:10.1172/JCI131241

Researchers from the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in collaboration with the Vetmeduni Vienna (including members of Richard Moriggl’s group), MedUni Vienna, Hannover Medical School, St. Gallen Cantonal Hospital and Bio-Cancer Treatment International Ltd identified a key mechanism that explains how antiviral immune responses can reprogram liver metabolism. 

The liver is a crucial organ for the systemic metabolism in our body. In addition to the turnover of biomolecules and drug metabolism, the liver removes toxic substances from the organism. The liver is thus a central metabolic hub in a healthy organism, but is also a central organ in the immune defence against infections - previous studies have shown how immune cells improve the liver metabolism to fight pathogens or cancer. Based on this, the authors of the article now published in the journal Immunity examined these immune metabolic changes during viral infection of mice. In addition to the expected inflammatory changes, the authors identified strong changes in liver metabolism. They were able to show that many central metabolic pathways, including the urea cycle, are suppressed when an infection occurs. The antiviral cytokine type I interferon (IFN-I) was then identified as a regulator of the urea cycle - after removal of the receptor for IFN-I from the surface of hepatocytes, the metabolic changes were no longer observed. This was a surprising observation that shows that IFN-I influences important biological processes during an infection. The results shed a new light on how the body's immune system has developed to regulate liver metabolism so that it controls T cell responses while reducing collateral tissue damage during infection.

Published in Immunity

Alexander Lercher*, Anannya Bhattacharya*, Alexandra M. Popa, Michael Caldera, Moritz F. Schlapansky, Hatoon Baazim, Benedikt Agerer, Bettina Gürtl, Lindsay Kosack, Peter Májek, Julia S. Brunner, Dijana Vitko, Theresa Pinter, Jakob-Wendelin Genger, Anna Orlova, Natalia Pikor, Daniela Reil, Maria Ozsvár-Kozma, Ulrich Kalinke, Burkhard Ludewig, Richard Moriggl, Keiryn L Bennett, Jörg Menche, Paul N. Cheng, Gernot Schabbauer, Michael Trauner, Kristaps Klavins and Andreas Bergthaler (*shared first authors)

Doi: https://doi.org/10.1016/j.immuni.2019.10.014