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CeMM Principal Investigator
Head, Molecular Discovery Platform (MDP)
 

Stefan Kubicek

Chemical biology and epigenetics

 

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 regulate transcription. Using innovative cell and chemical biological approaches, we identify and validate chromatin-modifying enzymes as therapeutic targets in cancer and diabetes, and develop novel chemical probes against these 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. At the same time, their direct link to transcriptional control makes chromatin-modifying enzymes a prime synthetic lethal target in many additional genetically defined cancers. Our goal is to systematically study the role of the approximately 400 chromatin modifying proteins in cancer development and progression, and identify key players as potentially druggable targets.

At the same time, we develop innovative phenotypic assays to identify and optimize small molecules that inhibit the epigenetic writers, readers and erasers. Such compounds will be used as chemical probes to study the function of these proteins, and could also for a starting point for further development of new anti-cancer drugs.

Cellular transdifferentiation in the endocrine pancreas 

Epigenetic modifications play important roles in cell type specification, and small molecule inhibitors of several chromatin modifying enzymes have been shown to increase the efficiency of cellular reprogramming. We hypothesize that targeting chromatin can contribute to the formation of therapeutically relevant cell types for regenerative medicine by promoting cellular transdifferentiation. 

We focus on the endocrine pancreas, where several developmentally closely related cell types from the insets of Langerhans. We use functional genomics and chemical biology probes to understand epigenetic plasticity between these cell types. Our goal is to convert other cell types to insulin-producing pancreatic beta-like cells, which could be used to develop an alternative approach for treating diabetes.

Biosketch

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 is working on the role of chromatin in the definition of cell types and cell states, in particular chromatin-modifying enzymes as synthetic lethal targets in cancer and chemical transdifferentiation to insulin-producing beta cells. In an ERC-funded project, the laboratory studies metabolic enzymes in the cell’s nucleus to test the hypothesis that small molecule metabolites shape chromatin structure and thus control gene expression and cell identity.

Selected Papers

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)

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

Licciardello, M. P. et al. NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation. Oncogene. 2015 Jul;34(29):3780-90. (abstract)

Mair, B., Kubicek, S. & Nijman, S. M. Exploiting epigenetic vulnerabilities for cancer therapeutics. Trends Pharmacol Sci. 2014 Mar;35(3):136-45. (abstract)

Kubicek, S. et al. Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells. Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5364-9. (abstract)

Fomina-Yadlin, D. et al. Small-molecule inducers of insulin expression in pancreatic alpha-cells. Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15099-104. (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)