How the structure of the genome shapes the immune system in health and disease
The 3D structure of our genome – the ‘epi-genome’ – is essential in determining the type and function of a cell. That is why the analysis of the epigenome facilitates deep insights into the developmental history of a cell, its current gene expression profile, and also its future destiny.
CD4+ T lymphocytes provide immunological protection by differentiation into various functional subtypes. However, they are also one of the main contributors to chronic inflammation and auto-immunity during disease. Therefore, our group focuses on the analysis and interpretation of epigenomic structures of CD4+ T lymphocytes in health and during chronic inflammatory diseases such as rheumatoid arthritis. These insights will not only highlight candidate genes involved in the disease-associated mis-differentiation of T cells, but will also pinpoint promising target elements for therapeutic intervention, as epigenetic modifications are in general reversible and hence, ‘druggable’.
In the last two years, one research focus of our group was the establishment of precise methods for the targeted manipulation of epigenetic switch regions in the genome of a living cell. For this, we established a state-of-the-art ‘epigenetic editing’ technique based on the CRISPR/Cas9-system in our lab and tested it successfully in primary human T cells. With this, we now aim at switching the functional program of a T cell at will, e.g. for the targeted re-programming of a pathogenic T cell to its normal counterpart. An additional application could be to equip T cell populations with a favorable function for their application in adoptive T cell therapy against auto-immune diseases.
A newly founded project (‘Leibniz Competition grant 2018’) in our group focuses on the epigenetic changes which occur in T cells during the aging process in humans (see page XX). This knowledge could impact on the development of clinical biomarkers for aging and pre-mature aging which is often associated with chronic inflammation.
Prof. Dr. Julia K. Polansky-Biskup
M. Sc. Christopher Kressler
M. Sc. Dania Hamo
M. Sc. Marcos Cases
Thomas Hildebrandt, Susanne Holtze (IZW, Berlin)
Jochen Hühn (HZI Braunschweig)
Birgit Sawitzki (Charite Berlin)
Alexander Scheffold (Cau Kiel)
Marcel Schulz (Uni Frankfurt)
Hans-Dieter Volk, Petra Reinke, Helena Radbruch (Charite Berlin)
Jörn Walter (Uni Saarbrücken)
Salhab A, Nordström K, Gasparoni G, Kattler K, Ebert P, Ramirez F, Arrigoni L, Müller F, Polansky JK, Cadenas C, G Hengstler J, Lengauer T, Manke T; DEEP Consortium, Walter J. (2018). A comprehensive analysis of 195 DNA methylomes reveals shared and cell-specific features of partially methylated domains. Genome Biol. 2018 Sep 28;19(1):150. doi: 10.1186/s13059-018-1510-5.
Nowak A, Lock D, Bacher P, Hohnstein T, Vogt K, Gottfreund J, Giehr P, Polansky JK, Sawitzki B, Kaiser A, Walter J, Scheffold A (2018). CD137+CD154- Expression As a Regulatory T Cell (Treg)-Specific Activation Signature for Identification and Sorting of Stable Human Tregs from In Vitro Expansion Cultures. Front Immunol. 7;9:199.
Szilagyi BA, Triebus J, Kressler C, de Almeida M, Tierling S, Durek P, Mardahl M, Menning A, Engelbert D, Floess S, Huehn J, Syrbe U, Walter J, Polansky JK*, Hamann A* (2017). Gut memories don´t fade: Expression of the gut homing receptor integrin α4β7 is stably imprinted in CD4+ memory T cells by epigenetic modification of regulatory regions in the itga4 locus. *shared last authorship. Mucosal Immunology, doi: 10.1038/mi.2017.7.
Schmidt F, Gasparoni N, Gasparoni G, Gianmoena K, Cadenas C, Polansky JK, Ebert P, Nordström K, Barann M, Sinha A, Fröhler S, Xiong J, Amirabad A, Ardakani F, Hutter B, Zipprich G, Felder B, Eils J, Brors B, Chen W, Hengstler J, Hamann A, Lengauer T, Rosenstiel P, Walter J, Schulz MH (2017). Combining transcription factor binding affinities with open chromatin data for accurate gene expression prediction. Nuclear Acid Res, 9;45(1):54-66.