Welcome to the " HIT " SFB: HDACs – Immunomodulation – T cells !
The special research program (SFB) “HDACs as regulators of T cell-mediated immunity in health and disease” is a newly established research network funded by the Austrian Science Fund. It is formed by an interdisciplinary consortium of eight research groups, of which seven are located in Vienna and one in Salzburg. The overall aim of this 8-year SFB research program and consortium is to provide an immunological and molecular rationale for using sub-class-specific and isoform-selective HDAC inhibitors in the treatment of T-cell-mediated diseases.
SFB project parts
Histone deacetylases (HDACs) are key epigenetic and genetic regulators during development and cell differentiation. HDACs control the acetylation status of histones and non-histone proteins, thus modulating chromatin function and the activity of non-histone protein targets, respectively. Pan-HDAC inhibitors (HDACi) are clinically used in the treatment of cancer. Preclinical data indicate that HDAC modulation might be also beneficial for the therapy of immunological diseases, although the use of existing pan-HDACi for these indications is limited by their side effects. We hypothesize that the usage of subclass-specific and/or isoform-selective HDACi, which is based on a better biological understanding of HDAC function, will avert limiting side effects and thereby broaden the clinical application spectrum of HDACi far beyond cancer. The common goal of this SFB is to provide a mechanistic molecular rationale for the development and application of isoform-selective HDACi for the treatment of T cell-mediated diseases, and to test essential regulatory roles of reversible lysine acetylation beyond histone modifications and epigenetic gene regulation in Th cells.
We will characterize epigenome, transcriptome, and acetyl-proteome profiles in Th lineage subsets and dissect how they are linked with Th effector functions in health and disease – including pathogenic fungal infections, skin inflammation, allergic airway inflammation, and experimental autoimmune diseases (EAE, arthritis) in mice and rheumatoid arthritis (RA) in humans (projects P02, P03, P04, P05, P06, P08).
We will generate comprehensive HDAC protein interaction maps and identify HDAC-dependent gene-regulatory networks in Th cells, and the overlay of global transcriptomics with proteomics data will reveal how distinct HDAC complexes and their post-translational modifications control complex formation, function as well as activity (projects P05, P07, P08, P09).
We will determine the impact of HDACs and HDACi on Th lineage stability and plasticity, integrating epigenome, transcription, acetyl-proteome and proteome data for Th lineages to dissect chromatin-mediated as well as non-chromatin functions of HDACs (project P01 together with entire SFB faculty).
• P01 – Wilfried ELLMEIER: SFB administration and platform coordination
• P02 – Christoph BOCK: Systems-level analysis of HDAC-dependent Th cell plasticity
• P03 – Michael BONELLI: HDACs as targets in systemic autoimmune disease patient
• P04 – Nicole BOUCHERON: HDACs and Th cell modulation in allergic airway inflammation
• P05 – Wilfried ELLMEIER: HDAC function in T cells beyond histone modifications
• P06 – Iris GRATZ: HDAC function in peripheral regulatory T cell biology
• P07 – Markus HARTL: HDAC-dependent interactomes and acetylomes in T cells
• P08 – Karl KUCHLER: HDACs and T cell-mediated antifungal immunity
• P09 – Christian SEISER: Regulation of HDAC complex function in T cells