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on signal transduction in disease conditions (e.g. during infection, transformation or drug treatment) is based on an outdated understanding of the homeostatic healthy condition.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.

Press Release

The Award Committee of the International Cytokine and Interferon Society (ICIS) selected the SFB PhD student Tobias Suske from Richard Moriggl’s lab for a Milstein Abstract Award in the amount of $500 in recognition of his presentation at Cytokines 2020 Virtual Meeting held at 1 - 4 November (https://seattle.cytokinesociety.org). The talk entitled “The Activating STAT5BN642H Driver Mutation Disrupts T Cell Development Progressing to T Cell Neoplasia” was given in the session “Structure-Function and Systems Biology of Cytokine Actions”.

The SFB members Birgit Strobl, Mathias Müller and Richard Moriggl show in complex mouse models and human cells the pivotal role of TYK2 in the development of severe organ damage during endotoxemia. Mechanistically the TYK2-dependent pathology was driven by murine caspase-11 (CASP11) or the human homolog CASP5 activity and the subsequent release of IL-1ß and IL-18.

Published in Cell Death & Differentiation

Andrea Poelzl, Caroline Lassnig, Sabine Tangermann, Dominika Hromadová, Ursula Reichart, Riem Gawish, Kristina Mueller, Richard Moriggl, Andreas Linkermann, Martin Glösmann, Lukas Kenner, Mathias Mueller & Birgit Strobl
TYK2 licenses non-canonical inflammasome activation during endotoxemia

https://doi.org/10.1038/s41418-020-00621-x

 

Using sophisticated genetically engineered mouse models the SFB members Birgit Strobl, Mathias Müller and Veronika Sexl further dissect the NK cell-intrinsic and -extrinsic requirements for STAT1a versus STAT1b in NK cell biology and tumor surveillance.

Published in Frontiers in Immunology

Kartin Meissl, Natalija Simonović, Lena Amenitsch, Agnieszka Witalisz-Siepracka, Klara Klein, Caroline Lassnig, Ana Puga, Claus Vogl, Andrea Poelzl, Markus Bosmann, Alexander Dohnal, Veronika Sexl, Mathias Müller & Birgit Strobl

STAT1 isoforms differentially regulate NK cell maturation and anti-tumour activity

https://doi.org/10.3389/fimmu.2020.02189

 

 

We are pleased to announce the second Cold Spring Harbor winter 2020 conference on JAK-STAT Pathways in Health & Disease, which will begin at 7:30 pm on Monday, April 6 and run through lunch on Thursday, April 9. 

Topics:

  • Jak-STAT Mutations and Genomic Functions
  • JAK-STAT Signaling in the Hematopoietic System
  • STAT3, Metabolism and Cancer
  • JAK-STAT Signaling and Regulation
  • Transcriptional and Epigenetic Regulation by STATs
  • JAK-STAT Inhibition

https://meetings.cshl.edu/meetings.aspx?meet=stats&year=20

cold spring harbor labratory

Therapeutic targeting of STAT3 by monobodies

An international consortium headed by the Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences ETH Lausanne collaborated with Veronika Sexl group members and developed the first monobodies targeted against STAT3. Monobodies are synthetic binding proteins engineered to selectively bind intracellular proteins – also those lacking an enzymatic domain. High affinity STAT3 monobodies were identified in a combinatorial phage and yeast display library sorting screen. The authors show selective interference of the monobodies with cellular STAT3 activity. This is an attractive therapeutic option due to STAT3’s homology with other STAT proteins that complicates the development of selective inhibitors.

Published in Nature Communications

Grégory La Sala, Camille Michiels, Tim Kükenshöner, Tania Brandstoetter, Barbara Maurer, Akiko Koide, Kelvin Lau, Florence Pojer, Shohei Koide, Veronika Sexl, Laure Dumoutier & Oliver Hantschel

Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains

Doi: https://doi.org/10.1038/s41467-020-17920-z

 

Nikolaus Fortelny and Christoph Bock of CeMM showed the usefulness of knowledge-primed neural networks (KPNNs) for the interpretation of single-cell RNA-seq data. They expect that the use of deep learning on biological networks will also be relevant in other areas of biomedicine analysing big data sets, including metabolomics, proteomics and cellular or cognitive networks.

Published in Genome Biology

Nikolaus Fortelny and Christoph Bock

Knowledge-primed neural networks enable biologically interpretable deep learning on single-cell sequencing data

Doi: https://doi.org/10.1186/s13059-020-02100-5

Special Issue ‚Targeting STAT3 and STAT5 in Cancer’ with Guest Editors Richard Moriggl (Vienna, AT), Patrick Gunning (Toronto, CA) and György Miklós Keserü (Budapest, HU). The Editorial of this Special Issue of Cancers (Basel) is now published: https://www.mdpi.com/2072-6694/12/8/2002.

The Special Issue contains various contributions of SFB members and associate members: https://www.mdpi.com/journal/cancers/special_issues/STAT_cancers

The mammalian immune system implements a remarkably effective set of mechanisms for fighting pathogens. Its main components are haematopoietic immune cells, including myeloid cells that control innate immunity, and lymphoid cells that constitute adaptive immunity. However, immune functions are not unique to haematopoietic cells, and many other cell types display basic mechanisms of pathogen defence. This study highlights the prevalence and organ-specific complexity of immune gene activity in non-haematopoietic structural cells, and it provides a high-resolution, multi-omics atlas of the epigenetic and transcriptional networks that regulate structural cells in the mouse.

Nature News and Views: https://www.nature.com/articles/d41586-020-01916-2

Article: https://www.nature.com/articles/s41586-020-2424-4