Simon Pöpsel

FM | CMMC

Dr. Simon Pöpsel CECAD Cologne
Dr. Simon Pöpsel

Principal Investigator

Research Areas

2
3

Molecular Mechanisms of Chromatin Regulation

We investigate proteins that regulate gene expression during differentiation and cellular stress. Focusing on transcription factors and chromatin-associated enzyme complexes, we decipher mechanisms of their activity regulation using biochemical and structural biology approaches.

Research Focus

Chromatin is the dynamic assembly of a cell’s DNA, associated proteins and nucleic acids. We are interested in the mechanisms by which gene regulation is coordinated through regulatory factors within this complex biochemical environment.

  • We particularly focus on transcription factors involved in cellular stress responses, as well as chromatin modifying enzymes. Using mammalian cultured cells, we are studying the molecular interactions that underly protein function and regulated enzymatic activities in the context of chromatin. We are reconstituting macromolecular complexes in vitro in order to determine the mechanisms of their assembly and enzymatic activity regulation. To this end, we are employing protein biochemistry and integrative structural biology approaches, including single-particle cryo-electron microscopy (cryo-EM) and cross-linking mass spectrometry.

Protein interactions and the molecular structure of multi-protein complexes are the key to understanding cellular protein function. Chromatin is at the heart of genome regulation, and we aim to elucidate molecular mechanisms controlling cell fate and stress responses in aging, development and disease.

Our Goals

Transcription factors and chromatin regulators such as histone modifying enzymes function in a complex biochemical environment. Key to their function is the faithful regulation of their enzymatic activities in time and space of the nucleus. These fundamental functional properties are controlled by means of dynamic molecular interactions and post-translational modifications. In our group, we aim to decipher these dynamic interactions as a basis of molecular regulation. This in turn helps us to rationally explain the physiological function of important chromatin regulators and may tell us how their dysfunction contributes to disease processes.

We use engineered cellular systems to identify novel molecular interactions and investigate the function of transcription factors and chromatin regulators in the complex context of a cell. This information is then used to reconstitute defined macromolecular complexes in vitro. Biochemical assays, as well as biophysical and structural biology approaches enable us to visualize and quantify protein-protein interactions and determine their impact on the structure and activity of multi-protein complexes.

  • We have a particular focus on the key stress regulator heat-shock factor 1 (HSF1);
  • HSF1 regulation and interactions on chromatin;
  • HSF1 interactions with chromatin modifying enzyme complexes.

Among the latter, we are interested in histone methyltransferases and demethylases that target lysine residues of histone proteins. By changing the biochemical properties of histones, which form the core of nucleosomes, the basic structural unit of chromatin, these enzymes are key players in regulating chromatin structure and function. We have successfully employed single-particle cryo-EM to visualize regulatory interactions of the human epigenetic regulator Polycomb Repressive Complex 2 (PRC2), leading to novel insights into the localized activity of this crucial factor in the genome. We have been successively expanding our tool set to include functional assays, interactomics and further structural methods such as cross-linking mass spectrometry.

Key Publications


  1. Sauer PV*, Pavlenko E*, Cookis T, Zirden LC, Renn J, Singhal A, Hunold P, Hoehne MN, van Ray O, Hänsel-Hertsch R, Sanbonmatsu KY, Nogales E# and Poepsel S#. 2023. Activation of automethylated PRC2 by dimerization on chromatin. BioRxiv (preprint), doi: doi.org/10.1101/2023.10.12.562141 _  (# = co-corresponding authors)
     
  2. Pavlenko, E., Ruengeler, T., Engel, P., Poepsel, S. 2022. Functions and interactions of mammalian KDM5 demethylases. (REVIEW) Frontiers in Genetics, doi: 10.3389/fgene.2022.906662.
     
  3. Poepsel, S, Kasinath, V and Nogales, E. 2018. Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes. Nature Structural & Molecular Biology. 25, 154-162.
     
  4. Kasinath V, Beck C, Sauer P, Poepsel S, Kosmatka J, Faini M, Toso D, Aebersold R, Nogales E. 2021. JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications. Science. Jan 22;371(6527):eabc3393. doi: 10.1126/science.abc3393.
     
  5. Kasinath, V., Faini, M., Poepsel, S., Reif, D., Feng X.A., Stjepanovic, G., Aebersold, R. and Nogales, E. 2018. Structures of human PRC2 with its cofactors AEBP2 and JARID2. Science. 359: 940-944.
Dr. Simon Pöpsel CECAD Cologne
Dr. Simon Pöpsel

Principal Investigator

Research Areas

2
3