Stefan Kubicek

The Kubicek Laboratory works in the field of Chemical Epigenetics, aiming to discover, develop, and characterize small molecules that impact cellular identity. Cell type and cell fate decisions are controlled by chromatin pathways that work in close connection to cellular metabolism to regulate gene expression. Using innovative approaches in cell biology and chemical biology, we identify and validate metabolic activities in the cell’s nucleus as therapeutic targets in cancer and diabetes, and develop novel chemical probes against these key epigenetic factors.
 

Chromatin pathways in cancer

Chromatin aberrations play causative roles in leukemia and solid tumors, where epigenetic modifiers are often aberrantly expressed or genetically altered. Their direct link to transcriptional regulation makes chromatin-modifying enzymes a prime synthetic lethal target in many genetically defined cancer types. We systematically study chromatin-modifying proteins and the metabolic pathways that provide cofactors for chromatin modification in cancer development and progression, with a particular focus on ATP-dependent chromatin remodeling processes.

At the same time, we develop innovative phenotypic assays to systematically identify and optimize small molecules that alter the abundance or subcellular localization of nuclear proteins. These compounds serve as chemical biology tools to investigate protein function and could be the starting point for epigenetics-based drug discovery.
 

Cellular transdifferentiation in the endocrine pancreas 

Epigenetic modifications play crucial roles in cell type specification, and small molecule inhibitors of chromatin-modifying enzymes have been shown to enhance the efficiency of cellular reprogramming. We hypothesize that targeting chromatin remodeling can support the generation of therapeutically relevant cell types for regenerative medicine by promoting cellular transdifferentiation.

Our research focuses on the endocrine pancreas, particularly on developmentally related cell types from the islets of Langerhans. We use functional genomics and chemical biology probes to explore epigenetic plasticity between these cell types. Our goal is to reprogram other cell types into insulin-producing pancreatic beta-like cells, offering a potential alternative treatment for diabetes through cell-based therapy.

Stefan Kubicek joined CeMM in 2010. He obtained an MSc in Synthetic Organic Chemistry from the Vienna University of Technology after writing a diploma thesis at ETH Zurich. For his PhD in Thomas Jenuwein’s lab at the IMP in Vienna, he changed fields to molecular biology and developed the first selective histone methyl transferase inhibitors. He then performed postdoctoral research, working on chemical biology with Stuart Schreiber at the Broad Institute of Harvard and MIT. At CeMM, Stefan Kubicek headed the Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, a public-private partnership between CeMM, Boehringer Ingelheim, and Haplogen, and is now the head of the CeMM Molecular Discovery Platform. The Kubicek lab studies chromatin, epigenetics and small molecules that change cell fates in oncology and diabetes with a particular focus on metabolism in the cell’s nucleus.

Reicher et al. Pooled multicolour tagging for visualizing subcellular protein dynamics. Nat Cell Biol. 2024 May;26(5):745-756. (abstract)

Enders et al. Pharmacological perturbation of the phase-separating protein SMNDC1  Nat Commun. 2023 Aug 16;14(1):4504. (abstract)

Casteels T et al. SMNDC1 links chromatin remodeling and splicing to regulate pancreatic hormone expression. Cell Rep. 2022 Aug 30;40(9):111288. (abstract)

Schick S, Grosche S, Kohl KE, et al. Acute BAF perturbation causes immediate changes in chromatin accessibility. Nat Genet. 2021 Mar;53(3):269-278. (abstract)

Reicher A et al. Pooled protein tagging, cellular imaging, and in situ sequencing for monitoring drug action in real time. Genome Res. 2020 Dec;30(12):1846-1855. (abstract)

Sdelci S et al. MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation. Nat Genet. 2019 Jun; 51(6):990-998. (abstract)

Schick et al. Systematic characterization of BAF mutations provides insights into intracomplex synthetic lethalities in human cancers. Nat Genet. 2019; 51(9):1399-1410. (abstract)

Licciardello, M. P. et al. A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor. Nat Chem Biol. 2017; 13(7):771-778. (abstract)

Li, J. et al. Artemisinins Target GABAA Receptor Signaling and Impair alpha Cell Identity. Cell. 2017 Jan 12;168(1-2):86-100.e15. (abstract)

Sdelci, S. et al. Mapping the chemical chromatin reactivation landscape identifies BRD4-TAF1 cross-talk. Nat Chem Biol. 2016 Jul;12(7):504-10. (abstract)

Li, J. et al. Single-cell transcriptomes reveal characteristic features of human pancreatic islet cell types. EMBO Rep. 2016 Feb;17(2):178-87. (abstract)

Kubicek, S. et al. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell. 2007 Feb 9;25(3):473-81. (abstract)