The complex interplay of genetics, development, and environment shapes cellular function and is at the heart of most human diseases. This talk will focus on the role of epigenetic cell states as “endophenotypes” and mediators of cell regulation in cancer and immunity. Epigenetic marks such as DNA methylation and changes in chromatin structure retain a precise memory of each cell’s developmental history, and they affect the cells’ future potential for responding to various intrinsic and environmental challenges.  

We are investigating the role of epigenetic cell states in immune regulation of non-hematopoietic, structural cells (Krausgruber et al. 2020 Nature), in rare genetic immunodeficiencies (Zhao et al. submitted) and inflammatory diseases (Halbritter et al. 2019 Cancer Discovery; Krausgruber et al. 2023 Immunity), in solid tumors (Klughammer et al. 2018 Nature Medicine; Sheffield et al. 2017 Nature Medicine), and in  organoid models in the context of the Human Cell Atlas (Bock et al. 2021 Nature Biotechnology). 

We also develop wet-lab and computational methods for dissecting biological function at scale. For example, we developed concepts and assays for high-content CRISPR screening (Bock et al. 2022 Nature Reviews Methods Primers), including the CROP-seq method for pooled CRISPR screening with single-cell RNA sequencing readout (Datlinger et al. 2017 Nature Methods) and the scifi-RNA-seq method cost-effective single-cell RNA-seq in 100,000s or millions of cells (Datlinger et al. 2021 Nature Methods); and machine learning methods for inferring regulatory cell states from single-cell data (Fortelny et al. 2020). 

Based on the insights gained from our investigation of epigenetic cell states in cancer and immunity, we are developing new approaches for molecular precision medicine that use epigenetic processes not only as biomarkers (Peneder et al. 2021 Nature Communications; Bock et al. 2012 Nature Reviews Cancer) and drug targets (Schmidl et al. 2019 Nature Chemical Biology), but also as effective modulators of future cell-based immunotherapies, where we epigenetically “program” cells for desired biological functions.