Junior Research Group|Dr. rer. nat. Christian Schmidl

Address

LIT - Leibniz Institute for Immunotherapy (former RCI)
c/o University Hospital Regensburg
F.-J.-Strauss Allee 11 | D-93053 Regensburg
phone: +49 (0) 941 944-18176

e-mail: christian.schmidl@ukr.de

Research Focus

Immune cells can recognize and kill tumor cells, but the complex tumor tissue often creates a suppressive environment that renders immune cells dysfunctional. Epigenetic mechanisms such as the packaging or modification of an immune cell’s DNA contribute to establish and maintain specific cellular states. These mechanisms are hence involved in “locking” cells in their unresponsive state, preventing treatments that aim at boosting immune cell’s function to fight tumor cells. We aim to understand and prevent the complex molecular processes that are involved in immune cell dysfunction to explore new treatment options.

Research Topic(s)

Chromatin and gene regulation in immune cells

We are interested how the non-coding part of our genome can interpret intrinsic and extrinsic cues to orchestrate differential gene expression in a tightly controlled spatiotemporal manner. After all, these astonishing mechanisms enable a single cell to develop to a complex organism with hundreds of specialized cell types, which all carry basically the same DNA sequence. Immune cells are an ideal system to study gene regulation, as many cell types are easily accessible from blood, and can be manipulated with tools that have been developed over decades.

Fig. 1: Chromatin profiles of leukemic cells from chronic lymphocytic leukemia patients. Active (H3K27ac and H3K4me1) and repressive (H3K27me3) histone modifications as well as chromatin accessibility (ATAC-seq) at a representative genomic locus is shown for two subgroups of the disease (uCLL = IGHV locus not mutated, mCLL = IGHV locus mutated). Compacted chromatin accessibility profiles are shown below for all analyzed samples (88 patients analyzed with ATAC-seq).

Single-cell methods

In the past, we only were able to sequence populations of cells. Currently, the development of single-cell sequencing methods has broadly widened our understanding of cell-to-cell variability, cellular plasticity and heterogeneity of cell. We are interested in refining and applying single-cell methods to study heterogeneous and highly dynamic cell populations such as immune and cancer cells.

Fig. 2: Encapsulation of barcoded beads in nanoliter droplets. The beads carry primers with barcode to bind polyA transcripts from co-encapsulated cells. During the cDNA synthesis, transcripts of the individual cells are labeled with different barcodes, which enables high-throughput single-cell RNA analyses.

Immune cell function in the tumor microenvironment

Interfering with co-inhibitory pathways can re-invigorate dysfunctional T cells and induce durable anti-tumor responses. However, tumor infiltrating lymphocytes (TILs) are a heterogeneous population of cells, and their true cellular state, stability and lineage relation remain to be elucidated to better predict treatment response, facilitate the development of new therapies, and to rationally design combinatory treatments. We want to use state-of-the art sequencing methods to understand underlying molecular causes of immune-cell (dys-)function in the tumor microenvironment with the aim to improve T cell targeting immunotherapies.

Staff

Manuela Kovacs-Sautter
Technische Assistentin
Phone: +49 (0) 941 - 944 - 38119
E-Mail: Manuela.Kovacs-Sautter(at)ukr.de

Marianna Maddaloni
PhD student
Phone: +49 (0) 941 - 944 - 38116
E-Mail: marianna.maddaloni(at)ukr.de

Elena Romero-Fernández
PhD student
Phone: +49 (0) 941 - 944 - 38178
E-Mail: Elena.Romero-Fernandez(at)ukr.de

Chiara Suriano
PhD student
Phone: +49 (0) 941 - 944 - 38119
E-Mail: chiara.suriano(at)ukr.de

Veronika Waas
Masters student

Theresa Wolf
Masters student

Publications

Delacher M, Simon M, Sanderink L, Hotz-Wagenblatt A, Wuttke M, Schambeck K,Schmidleithner L, Bittner S, Pant A, Ritter U, Hehlgans T, Riegel D, SchneiderV, Groeber-Becker FK, Eigenberger A, Gebhard C, Strieder N, Fischer A, Rehli M,Hoffmann P, Edinger M, Strowig T, Huehn J, Schmidl C, Werner JM, Prantl L, BrorsB, Imbusch CD, Feuerer M. Single-cell chromatin accessibility landscapeidentifies tissue repair program in human regulatory T cells. Immunity. 2021 Apr13;54(4):702-720.e17. doi: 10.1016/j.immuni.2021.03.007. Epub 2021 Mar 30.
Drexler K, Schmidt KM, Jordan K, Federlin M, Milenkovic VM, Liebisch G,Artati A, Schmidl C, Madej G, Tokarz J, Cecil A, Jagla W, Haerteis S, Aung T,Wagner C, Kolodziejczyk M, Heinke S, Stanton EH, Schwertner B, Riegel D, WetzelCH, Buchalla W, Proescholdt M, Klein CA, Berneburg M, Schlitt HJ, Brabletz T,Ziegler C, Parkinson EK, Gaumann A, Geissler EK, Adamski J, Haferkamp S,Mycielska ME. Cancer-associated cells release citrate to support tumourmetastatic progression. Life Sci Alliance. 2021 Mar 23;4(6):e202000903.
Minderjahn J, Schmidt A, Fuchs A, Schill R, Raithel J, Babina M, Schmidl C, Gebhard C, Schmidhofer S, Mendes K, Ratermann A, Glatz D, Nützel M, Edinger M, Hoffman P, Spang R, Längst G, Imhof A, Rehli M. Mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1. 2020. Nat Commun 11: 402
Rendeiro AF*, Krausgruber T*, Fortelny N, Zhao F, Penz T, Farlik M, Schuster LC, Nemc A, Tasnády S, Réti M, Mátrai Z, Alpar D#, Bödör C#, Schmidl C#, Bock C#. Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia. 2020. Nat Commun 11:577
Feldker N, Ferrazzi F, Schuhwerk H, Widholz SA, Guenther K, Frisch I, Jakob K, Kleemann J, Riegel D, Bönisch U, Lukassen S, Eccles RL, Schmidl C, Stemmler MP, Brabletz T, Brabletz S. 2020. Genome-wide cooperation of EMT transcription factor ZEB1 with YAP and AP-1 in breast cancer. EMBO 1;39(17):e103209
Krausgruber T*, Fortelny N*, Fife-Gernedl V, Senekowitsch M, Schuster LC, Lercher A, Nemc A, Schmidl C, Rendeiro AF, Bergthaler A, Bock C. 2020. Structural cells are key regulators of organ-specific immune response. Nature 583:296-302
Hubmann R, Schnabl S, Araghi M, Schmidl C, Rendeiro AF, Hilgarth M, Demirtas D, Farghaly A, Staber PB, Valent P, Zielinski C, Jäger U, Shehata M. 2020. Targeting Nuclear NOTCH2 by Gliotoxin Recovers a Tumor-Suppressor NOTCH3 Activity in CLL. Cells 9(6):E1484
Jühling F*, Hamdane N*, Crouchet E*, Li S*, El Saghire H, Mukherji A, Fujiwara N, Oudot MA, Thumann C, Saviano A, Roca Suarez AA, Goto K, Masia R, Sojoodi M, Arora G, Aikata H, Ono A, Tabrizian P, Schwartz M, Polyak SJ, Davidson I, Schmidl C, Bock C, Schuster C, Chayama K, Pessaux P, Tanabe KK, Hoshida Y, Zeisel MB, Duong FH, Fuchs BC, Baumert TF. 2020. Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma. Gut 26:gutjnl-2019-318918
Delacher M*, Imbusch C*, Hotz-Wagenblatt A, Mallm J, Bauer K, Simon M, Riegel D, Rendeiro A, Bittner S, Sanderink L, Pant A, Schmidleithner L, Braband K, Echtenachter B, Fischer A, Giunchiglia V, Hoffmann P, Edinger M, Bock C, Rehli M, Brors B, Schmidl C#, Feuerer M#. Precursors for nonlymphoid-tissue Treg cells reside in secondary lymphoid organs and are pro-grammed by the transcription factor BATF. Immunity. 2020 Jan 2. pii: S1074-7613(19)30498-4.
Minderjahn J, Schmidt A, Fuchs A, Schill R, Raithel J, Babina M, Schmidl C, Gebhard C, Schmidhofer S, Mendes K, Ratermann A, Glatz D, Nützel M, Edinger M, Hoffman P, Spang R, Längst G, Imhof A, Rehli M. 2020. Mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1. Nat Commun 11: 402Rendeiro AF*, Krausgruber T*, Fortelny N, Zhao F, Penz T, Farlik M, Schuster LC, Nemc A, Tasnády S, Réti M, Mátrai Z, Alpar D#, Bödör C#, Schmidl C#, Bock C#. 2019. Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia. Accepted at Nature Communications. Preprint available at bioRxiv doi:10.1101/597005: 597005.
Sdelci S, Rendeiro AF, Rathert P, You W, Lin JG, Ringler A, Hofstatter G, Moll HP, Gurtl B, Farlik M, Schick S, Klepsch F, Oldach M, Buphamalai P, Schischlik F, Majek P, Parapatics K, Schmidl C, Schuster M, Penz T, Buckley DL, Hudecz O, Imre R, Wang SY, Maric HM, Kralovics R, Bennett KL, Muller AC, Mechtler K, Menche J, Bradner JE, Winter GE, Klavins K, Casanova E, Bock C, Zuber J, Kubicek S. 2019. MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation. Nat Genet 51: 990-998.
Schmidl C*, Vladimer GI*, Rendeiro AF*, Schnabl S*, Krausgruber T, Taubert C, Krall N, Pemovska T, Araghi M, Snijder B, Hubmann R, Ringler A, Runggatscher K, Demirtas D, de la Fuente OL, Hilgarth M, Skrabs C, Porpaczy E, Gruber M, Hoermann G, Kubicek S, Staber PB, Shehata M#, Superti-Furga G#, Jager U#, Bock C#. 2019. Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL. Nat Chem Biol doi:10.1038/s41589-018-0205-2.
Schick S, Rendeiro AF, Runggatscher K, Ringler A, Boidol B, Hinkel M, Majek P, Vulliard L, Penz T, Parapatics K, Schmidl C, Menche J, Boehmelt G, Petronczki M, Muller AC, Bock C, Kubicek S. 2019. Systematic characterization of BAF mutations provides insights into intracomplex synthetic lethalities in human cancers. Nat Genet 51: 1399-1410.
Hamdane N*, Juhling F*, Crouchet E, El Saghire H, Thumann C, Oudot MA, Bandiera S, Saviano A, Ponsolles C, Roca Suarez AA, Li S, Fujiwara N, Ono A, Davidson I, Bardeesy N, Schmidl C, Bock C, Schuster C, Lupberger J, Habersetzer F, Doffoel M, Piardi T, Sommacale D, Imamura M, Uchida T, Ohdan H, Aikata H, Chayama K, Boldanova T, Pessaux P, Fuchs BC, Hoshida Y, Zeisel MB, Duong FHT, Baumert TF. 2019. HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response. Gastroenterology 156: 2313-2329 e2317.
Gustafsson C, De Paepe A, Schmidl C, Mansson R. 2019. High-throughput ChIPmentation: freely scalable, single day ChIPseq data generation from very low cell-numbers. BMC Genomics 20: 59.
Delacher M, Schmidl C, Herzig Y, Breloer M, Hartmann W, Brunk F, Kagebein D, Trager U, Hofer AC, Bittner S, Weichenhan D, Imbusch CD, Hotz-Wagenblatt A, Hielscher T, Breiling A, Federico G, Grone HJ, Schmid RM, Rehli M, Abramson J, Feuerer M. 2019. Rbpj expression in regulatory T cells is critical for restraining TH2 responses. Nat Commun 10: 1621.
Schnell A, Schmidl C, Herr W, Siska PJ. 2018. The Peripheral and Intratumoral Immune Cell Landscape in Cancer Patients: A Proxy for Tumor Biology and a Tool for Outcome Prediction. Biomedicines 6.
Schmidl C, Delacher M, Huehn J, Feuerer M. 2018. Epigenetic mechanisms regulating T-cell responses. J Allergy Clin Immunol 142: 728-743.
Noguchi S, Arakawa T, Fukuda S, Furuno M, Hasegawa A, Hori F, Ishikawa-Kato S, Kaida K, et al. 2017. FANTOM5 CAGE profiles of human and mouse samples. Sci Data 4: 170112.
Datlinger P, Rendeiro AF§, Schmidl C§, Krausgruber T, Traxler P, Klughammer J, Schuster LC, Kuchler A, Alpar D, Bock C. 2017. Pooled CRISPR screening with single-cell transcriptome readout. Nat Methods 14: 297-301.
Rendeiro AF*, Schmidl C*, Strefford JC*, Walewska R, Davis Z, Farlik M, Oscier D, Bock C. 2016. Chromatin accessibility maps of chronic lymphocytic leukaemia identify subtype-specific epigenome signatures and transcription regulatory networks. Nat Commun 7.
Feichtinger J, Hernandez I, Fischer C, Hanscho M, Auer N, Hackl M, Jadhav V, Baumann M, Krempl PM, Schmidl C, Farlik M, Schuster M, Merkel A, Sommer A, Heath S, Rico D, Bock C, Thallinger GG, Borth N. 2016. Comprehensive Genome and Epigenome Characterization of CHO Cells in Response to Evolutionary Pressures and Over Time. Biotechnol Bioeng 113: 2241-2253.
Tomazou EM*, Sheffield NC*, Schmidl C, Schuster M, Schonegger A, Datlinger P, Kubicek S, Bock C#, Kovar H#. 2015. Epigenome mapping reveals distinct modes of gene regulation and widespread enhancer reprogramming by the oncogenic fusion protein EWS-FLI1. Cell Rep 10: 1082-1095.
Tausendschon M, Rehli M, Dehne N, Schmidl C, Doring C, Hansmann ML, Brune B. 2015. Genome-wide identification of hypoxia-inducible factor-1 and -2 binding sites in hypoxic human macrophages alternatively activated by IL-10. Biochim Biophys Acta 1849: 10-22.
Schmidl C*, Rendeiro AF*, Sheffield NC, Bock C. 2015. ChIPmentation: fast, robust, low-input ChIP-seq for histones and transcription factors. Nat Methods 12: 963-965.
Joshi A, Pooley C, Freeman TC, Lennartsson A, Babina M, Schmidl C, Geijtenbeek T, the FC, Michoel T, Severin J, Itoh M, Lassmann T, Kawaji H, Hayashizaki Y, Carninci P, Forrest AR, Rehli M, Hume DA. 2015. Transcription factor, promoter, and enhancer utilization in human myeloid cells. J Leukoc Biol doi:10.1189/jlb.6TA1014-477RR.
Schmidl C, Renner K, Peter K, Eder R, Lassmann T, Balwierz PJ, Itoh M, Nagao-Sato S, Kawaji H, Carninci P, Suzuki H, Hayashizaki Y, Andreesen R, Hume DA, Hoffmann P, Forrest AR, Kreutz MP, Edinger M, Rehli M, consortium F. 2014. Transcription and enhancer profiling in human monocyte subsets. Blood 123: e90-99.
Schmidl C, Hansmann L, Lassmann T, Balwierz PJ, Kawaji H, Itoh M, Kawai J, Nagao-Sato S, Suzuki H, Andreesen R, Hayashizaki Y, Forrest AR, Carninci P, Hoffmann P, Edinger M, Rehli M, consortium F. 2014. The enhancer and promoter landscape of human regulatory and conventional T-cell subpopulations. Blood 123: e68-78.
The FANTOM Consortium, Forrest AR*, Kawaji H*, Rehli M*, Baillie JK*, de Hoon MJ, Haberle V, Lassmann T, et al: A promoter-level mammalian expression atlas. Nature 2014, 507:462-470.
Andersson R*, Gebhard C*, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, Chen Y, Zhao X, Schmidl C, Suzuki T, et al: An atlas of active enhancers across human cell types and tissues. Nature 2014, 507:455-461.
Pham TH, Minderjahn J, Schmidl C, Hoffmeister H, Schmidhofer S, Chen W, Langst G, Benner C, Rehli M. 2013. Mechanisms of in vivo binding site selection of the hematopoietic master transcription factor PU.1. Nucleic Acids Res 41: 6391-6402.
Hansmann L, Schmidl C, Kett J, Steger L, Andreesen R, Hoffmann P, Rehli M, Edinger M. 2012. Dominant Th2 differentiation of human regulatory T cells upon loss of FOXP3 expression. J Immunol 188: 1275-1282.
Schmidl C*, Hansmann L*, Andreesen R, Edinger M, Hoffmann P, Rehli M. 2011. Epigenetic reprogramming of the RORC locus during in vitro expansion is a distinctive feature of human memory but not naive Treg. Eur J Immunol 41: 1491-1498.
Hansmann L*, Schmidl C*, Boeld TJ*, Andreesen R, Hoffmann P, Rehli M, Edinger M. 2010. Isolation of intact genomic DNA from FOXP3-sorted human regulatory T cells for epigenetic analyses. Eur J Immunol 40: 1510-1512.
Schmidl C, Klug M, Boeld TJ, Andreesen R, Hoffmann P, Edinger M, Rehli M. 2009. Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res 19: 1165-1174.
Neumeier M, Weigert J, Schaffler A, Weiss TS, Schmidl C, Buttner R, Bollheimer C, Aslanidis C, Scholmerich J, Buechler C. 2006. Aldehyde oxidase 1 is highly abundant in hepatic steatosis and is downregulated by adiponectin and fenofibric acid in hepatocytes in vitro. Biochem Biophys Res Commun 350: 731-735.

*, §, # = equal contributions