Sebastian Deindl

Dynamic Structural Biology of Genome-Interacting Protein Machines

University of Tübingen
IMPRS Faculty

Vita

Diploma in Biochemistry, University of Tübingen, 2004
PhD studies at the University of California, Berkeley, 2004–2009
Jane Coffin Childs Postdoctoral Fellow at Harvard University, 2009–2014
Assistant, Associate, and Full Professor at Uppsala University, 2014–current
Alexander von Humboldt Professor and W3 Chair in Dynamic Structural Biology at the University of Tübingen since 2026

Research Interest

Figure 1. Artistic representation of a protein machine operating on a nucleosome. High-resolution structural snapshots obtained by cryo-electron microscopy reveal how such molecular machines engage chromatin, while single-molecule fluorescence microscopy makes it possible to monitor their dynamic motions and transient functional states in real time.

Figure 1. Artistic representation of a protein machine operating on a nucleosome. High-resolution structural snapshots obtained by cryo-electron microscopy reveal how such molecular machines engage chromatin, while single-molecule fluorescence microscopy makes it possible to monitor their dynamic motions and transient functional states in real time.

We investigate how biomolecular structure and dynamics give rise to function in genome-interacting protein machines. To this end, our group develops novel single-molecule fluorescence approaches and integrates them with structural biology, particularly cryo-electron microscopy, as well as biochemical methods. By combining these complementary approaches, we aim to bridge static structural snapshots with the dynamic behavior of individual molecules and develop a quantitative understanding of biomolecular mechanisms. Our research focuses on nucleic acid-interacting proteins and protein assemblies, particularly those that regulate gene expression in chromatin. These molecular machines often act through transient, heterogeneous, and highly dynamic mechanisms that are shaped by the sequence, structure, and chromatin context of their substrates. As a result, their function is difficult to understand from static structures or ensemble-averaged measurements alone.

https://www.youtube.com/watch?v=NxZY58axXKE

Image depicting multiplexed single-molecule characterization at the library scale (MUSCLE) developed in the lab. — Figure 2. Multiplexed single-molecule fluorescence approaches, such as MUSCLE (*multiplexed single-molecule characterization at the library scale*) developed in our lab, connect molecular identity to dynamic behavior across millions of individual molecules. By enabling parallel measurements across large DNA libraries or barcoded molecular populations, MUSCLE provides a powerful route to uncover how sequence and molecular context shape biomolecular mechanisms.

Figure 2. Multiplexed single-molecule fluorescence approaches, such as MUSCLE (*multiplexed single-molecule characterization at the library scale*) developed in our lab, connect molecular identity to dynamic behavior across millions of individual molecules. By enabling parallel measurements across large DNA libraries or barcoded molecular populations, MUSCLE provides a powerful route to uncover how sequence and molecular context shape biomolecular mechanisms.

To address this challenge, we develop and apply new single-molecule fluorescence methods, including highly multiplexed approaches that allow us to follow molecular processes across millions of individual molecules and thousands of DNA sequences or barcoded entities. These approaches make it possible to connect molecular identity, sequence context, structure, dynamics, and function at large scale. By integrating structural analysis with advanced single-molecule methods, we aim to address fundamental questions in chromatin biology. In eukaryotes, DNA is packaged into chromatin, which enables differential genome organization and gives rise to diverse transcriptional programs from a single genetic blueprint. Chromatin states must be established, maintained, interpreted, and remodeled with high precision, yet the molecular mechanisms underlying these processes remain incompletely understood. Misregulation of these processes is strongly linked to developmental disorders and diseases such as cancer.

Link to faculty webpage:

https://uni-tuebingen.de/fakultaeten/mathematisch-naturwissenschaftliche-fakultaet/fachbereiche/interfakultaere-einrichtungen/ifib/arbeitsgruppen/gruppen-a-f/deindl/

Available PhD Projects

Currently not recruiting doctoral researchers.

Selected Reading

Kapanidis AN, Muras L, Sreenivasa K, Hazra JP, van Noort J, Joo C and Deindl S. (2026). From sequence to function: Bridging single-molecule kinetics and molecular diversity. Science. doi: 10.1126/science.adv4503
Aguirre Rivera J, Mao G, Sabantsev A, Panfilov M, Hou Q, Lindell M, Chanez C, Ritort F, Jinek M and Deindl S. (2024). Massively parallel analysis of single-molecule dynamics on next-generation sequencing chips. Science. doi: 10.1126/science.adn5371
Bacic L, Gaullier G, Mohapatra J, Mao G, Brackmann K, Panfilov M, Liszczak G, Sabantsev A and Deindl S. (2024). Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1. Nature Communications. doi: 10.1038/s41467-024-45237-8
Marklund E, van Oosten B, Mao G, Amselem E, Kipper K, Sabantsev A, Emmerich A, Globisch D, Zheng X, Lehmann LC, Berg OG, Johansson M, Elf J and Deindl S. (2020). DNA surface exploration and operator bypassing during target search. Nature. doi: 10.1038/s41586-020-2413-7
Bowman GD and Deindl S. (2019). Remodeling the genome with DNA twists. Science. doi: 10.1126/science.aay4317