The initiative SFB-JakStat is a special research programme granted by the Austrian Science Fund FWF from 2006 to 2016. In 2017 the programme has been relaunched with a funding period of maximum eight years.
It pools existing resources by creating a veritable JakStat-platform that is amongst the largest in Europe, Asia, Australia or North America. This state-of-the-art scientific network consists of six basic research-oriented groups from three different universities and two translational research performing institutes, namely the University of Veterinary Medicine Vienna including its core facility Biomodels Austria, the Max F. Perutz Laboratories of the University of Vienna and the Medical University of Vienna, the Ludwig Boltzmann Institute for Cancer Research and the Research Center for Molecular Medicine of the Austrian Academy of Sciences.
The new initiative SFB-JakStat ‚Monarchies and Hierarchies in Shaping Chromatin Landscapes’ Offers 10 PhD Positions:
Special Research Program FWF SFB F61 ‘Monarchies and Hierarchies in Shaping Chromatin Landscapes’ Offers PhD Positions
The JAK-STAT signaling pathway is central in cellular homeostasis and development and controls inflammation, infection and cancer. The Viennese JAK-STAT community recently attracted funding from the FWF for a Special Research Programme (SFB) on JAK-STAT signaling, chromatin remodeling and disease (www.jak-stat.at). It is now advertising 10 PhD positions to promising young scientists who wish to work at the cutting edge of research into the interface between inflammation, immunity and cancer.
The SFB provides a productive, tightly interconnected network for the long-term and interdisciplinary investigation of complex topics. It is hosted by the University of Veterinary Medicine Vienna (www.vetmeduni.ac.at; Richard Moriggl, Mathias Müller, Veronika Sexl) and involves CeMM Austrian Academy of Sciences (www.cemm.at; Christoph Bock), MFPL University of Vienna (www.mfpl.ac.at; Thomas Decker) and the Medical University of Vienna (www.meduniwien.ac.at; Sylvia Knapp).
The SFB is studying principles that underlie switches in transcription directed by the chromatin landscape and 3D structure, such as those that occur in normal and aberrant development, in the reaction to infection and in carcinogenesis. Consortium members have expertise in areas as wide-ranging as immunity, inflammation, hematopoietic malignancies, pharmacogenomics, epigenetics, bioinformatics, ‘disease-tailored’ mouse models and genome editing. The group’s mission is to pave the way for novel therapeutic possibilities, especially with regard to personalized medicine.
PhD students will have the opportunity to perform research at the cutting edge of interdisciplinary molecular medicine and will be trained by the entire consortium and associated faculty, enabling them to help shape the future of pathway medicine. They will address key biomedical questions. The available resources and support will give them the freedom to experiment and to develop their scientific skills. An extensive programme of courses in complementary skills is offered.
The PhD positions are open to students who hold a Master’s degree or equivalent (four years BSc Honors with thesis) in biosciences, biochemistry, or related fields. Given the importance of analysing large datasets in all projects, basic knowledge of computational biology and statistics are highly desirable. Salary according to FWF regulations. Starting date as soon as possible. For further information about the principle investigators and individual project parts see www.jak-stat.at.
Please send your application including a motivation letter, a CV, certificates, and names and addresses of 2-3 references (including telephone number and e-mail address) or letters of recommendation by e-mail to:
Closing date: March 2nd 2017
SFB F61 ‚Monarchies and Hierarchies in Shaping Chromatin Landscapes’ – Overall Scientific Concept and Individual Project Parts
The scientific questions fall into two broad biological categories, i.e. immunity and cancer: area 1 determines how STATs and/or JAKs contribute to the dynamic chromatin changes associated with the polarization of NK cells, T helper (Th) cells and macrophages and with immune responses and area 2 dissects how the JAK-STAT axis influences stable changes associated with tumourigenesis in myeloid versus lymphoid transformation and in various forms of leukaemia.
The consortium will focus on haematopoietic cells (macrophages, NK cells, T cells) with respect to immune-relevant stimuli (area 1) and conditions promoting malignant transformation (area 2). It has immediate access to a unique collection of genetically engineered STAT and JAK mutant mice (> 50 strains).
The initial aims are the determination of
• steady-state chromatin architecture (3D structure, nucleosome positions, DNA methylation, histone modification and STAT binding sites) of the cellular systems;
• dynamic chromatin changes induced by immune challenges or tumourigenesis under the influence of (non)canonical JAKs and STATs;
• hierarchical levels of transcriptome control on which STATs impact.
Our vision is the establishment of chromatin landscapes as overarching biomarkers for cellular states and their alterations during immune responses and disease progression. A precise understanding of chromatin landscapes would allow the functional assessment of their importance in cell and animal models. It would pave the way for novel combinations of drugs and for the identification of new drug targets and would possibly help establish the concept of druggable chromatin.
Christoph Bock (P02 CB) ‘Dissecting cell type-specific chromatin dynamics driven by oncogenic JAK-STAT signalling’ is embedded in area 2 and tests the influence of STAT3 and 5 on DNA methylation, histone modifications and nucleosome positioning.
JAK-STAT signalling is vital for the development, survival and response of immune cells. Intriguingly, members of the JAK-STAT pathway are frequently mutated in cancer and are known to drive several haematopoietic malignancies. Based on our observation that key regulatory regions of myeloid development are specifically hypermethylated in the lymphoid lineage, we hypothesize that oncogenic transformation by aberrant STAT activity is dependent on a permissive epigenome. To identify cell type-specific differences in the response to JAK-STAT signalling, we will isolate specific lymphoid and myeloid cell populations from wild-type and STAT-deficient mice and analyse their epigenome and transcriptome response upon treatment with STAT-activating cytokines. The cross-talk between JAK-STAT signalling and the epigenome will be further investigated in cooperation with P07 VS using in vivo transplants of retrovirally transformed bone marrow harbouring known STAT3 mutations, which will provide a basis for dissecting the epigenome dynamics of oncogenic transformation. In the same way, we will work with P05 RM on the STAT5BN642H mutant mouse. The ensuing insights into STAT-induced oncogenic reprogramming of the epigenome could potentially contribute to the development of precision therapies for STAT-driven leukaemia. http://cemm.at/research/groups/christoph-bock-group/
Thomas Decker (P03 TD) ‘Hierarchical layers of gene control in the innate response to infection’ is central to area 1 and investigates the cooperation of STAT1/2 with other TFs and their influence on long-range chromosomal interactions and on histone modifications.
Infection causes drastic shifts in gene expression towards antimicrobial gene signatures. We will examine the transcriptional response of bone marrow macrophages to infection with the intracellular bacterium Listeria monocytogenes (Lm), focusing on changes to diagnostic chromatin modifications, DNA accessibility and intra- as well as interchromosomal interactions. We will concentrate on STAT-dependent type I interferon (IFN-I)-induced genes (ISG) and a group of ‘synergy genes’, whose promoter activation requires cooperative activity of the IFN-I/STAT and NFκB pathways. ISG and synergy genes represent distinct regulatory entities and we shall examine their chromatin landscapes for differences before and following infection. We shall test the hypothesis that the need for diverse regulatory input to ISG and synergy genes derives from different chromosomal topologically associated domains (TAD). Genome editing will be used to validate the functional relevance of enhancers that regulate ISG and synergy genes. Our long-term goal is to derive a comprehensive view of how STATs determine genome structure and chromatin landscapes and thereby coordinating gene transcription during microbial infection. https://www.mfpl.ac.at/de/gruppen/mfpl-gruppen/group-info/decker.html
Sylvia Knapp (P04 SK) ‘L-MAC: Probing the STAT impact on homeostatic lung macrophage signatures’ contributes to area 1. The research relates to the impact of the availability of STAT1/3 on chromatin remodelling.
Macrophages are prototypic resident immune cells that shape a range of effects, from safeguarding homeostasis to inflammation, based on their remarkable plasticity and ability to adjust quickly to changing environmental cues. A panel of transcription factors and epigenetic regulators in conjunction with STAT1/3/6 define the state of the resident macrophages. Recent advances in transcriptional and chromatin profiling have opened an entirely new avenue to investigate the environmental cues that define tissue-specific macrophage profiles in health and their dynamics upon stress/disease.
We aim to analyse the role of STAT1/3 in the in vivo homeostatic signature of alveolar macrophages (AM) and to investigate the hierarchy of changes on acute perturbations of homeostasis (such as after birth). We shall determine the transcriptional profile (RNASeq) and enhancer landscape of healthy adult pulmonary macrophages by genome-wide mapping of selected histone marks and open chromatin (Chip-Seq, ATAC-Seq). A detailed map of transcriptional and enhancer landscapes of AMs, and insights into the role of STAT1/3, will provide an excellent basis for understanding the memory potential and functional impact of perturbations and will open ways to develop drugs to modulate macrophage activity in inflammatory diseases. http://cemm.at/research/groups/sylvia-knapp-group/
Richard Moriggl (P05 RM) ‘Chromatin remodelling through oncogenic STAT5 in Peripheral T Cell Leukaemia and Lymphoma’ is central to area 2 and focuses on the doses of STAT5 that lead to potential TF cooperativity and on changes in chromatin accessibility.
STAT5 is hyperactivated in a variety of haematopoietic tumours, prominently in Peripheral T-Cell Leukaemia and Lymphoma (PTCL). Hyperactivation of STAT5 is caused either by overexpression of STAT5A or by a somatic gain-of-function mutation in STAT5B (STAT5BN642H), most frequently found in PTCL. Given the proposed interplay of STAT5 with epigenetic modulators, we hypothesize that high level of activated STAT5 (=pSTAT5Y694, pYSTAT5) form a disease-propagating epigenetic landscape. To study the influence of STAT5 on these oncogenic rearrangements, we have created two transgenic mouse models expressing high levels of pYSTAT5, cSTAT5AFlagHIGH and STAT5BN642H mice, and two control lines expressing physiological levels of STAT5A or STAT5B. The cSTAT5AFlagHIGH and STAT5BN642H mice develop a PTCL-like disease. We will compare STAT5-dependent epigenomes and interactomes to gain insights into pYSTAT5-dependent chromatin structures that are specific for disease. Our long term visions are (i) to understand how STAT5 influences the chromatin landscape, (ii) to unravel how this influence is changed during malignant T-cell transformation and (iii) to identify critical cooperativity partners of STAT5 in neoplastic T cells to open novel therapeutic avenues. http://lbicr.lbg.ac.at/en/moriggl-research-group
Mathias Müller (P06 MM) ‘(Non-)canonical TYK2 – a monarch in signalling into chromatin?’ contributes to area 1 and investigates the impact of enzymatically active and inactive TYK2 on DNA methylation and chromatin remodelling.
In the canonical linear JAK-STAT pathway, receptor-associated JAKs signal through STAT proteins into the nucleus. The recent development of inhibitors of JAK activity to treat malignancies and autoinflammatory/autoimmune diseases has led to a renewed interest in kinase-independent and/or non-receptor-associated functions of JAKs. Both mouse and human TYK2 have been shown to exert functions independent of their enzymatic activity, although with the exception of cytokine receptor scaffolding, these are ill-defined. We will characterize the molecular networks targeted by kinase-inactive TYK2 that regulate epigenetic (DNA methylation, chromatin landscape) and transcriptional changes under homeostatic and diseased conditions. We will build on the findings that kinase-inactive TYK2 drives NK-cell maturation and function and redirects CD8+ T-cell antitumour immunity and on evidence that at least some of these TYK2 functions are independent of STATs. http://www.jak-stat.at/index.php?id=23
Veronika Sexl (P07 VS) ‘Partners in crime: STAT3 and CDK6 control transformation in hematopoietic cells’ is central to area 2 and tests the stepwise cooperativity of STAT3 and TFs in gene induction and histone modification.
We propose a novel mode by which STAT3 regulates the chromatin landscape in transformed haematopoietic cells in cooperation with the cell cycle regulator CDK6. We shall test this notion by means of BCR ABL+ and NPM-ALK+ tumours. If either STAT3 or CDK6 is absent, tumour formation is severely reduced. Our preliminary studies suggest a tight interaction of STAT3 and CDK6 on chromatin, which we intend to investigate further. Our investigations will include the STAT3 mutations that have been repeatedly found in human lymphoid malignancies. These clinically relevant STAT3 mutations will be studied in model cell lines and in vitro and in vivo in B and T lymphoid cells. We shall test their ability to propagate leukaemia, their epigenetic landscape and their interaction with CDK6. The work should reveal a novel layer of regulation of STAT3, mediated via its interaction with CDK6 and might open a novel therapeutic avenue to interfere with STAT3´s function. http://www.vetmeduni.ac.at/de/pharmakologie-und-toxikologie/home/
SFB-JakStat presents combined efforts to address the role of Jaks and/or Stats in two important categories of disease:
infection/inflammation and cancer. An intimate inter-relationship between both processes is emerging from recent literature. Hence, particular efforts will be made - and present a main raison d'etre for the consortium - to understand Jaks and Stats signals and mechanisms linking infection, inflammation and cancer.