Sir Henry Dale Fellow
Philipp Voigt is a Sir Henry Dale Fellow at the Wellcome Centre for Cell Biology. Work in his lab aims to determine how different histone modifications interact to regulate gene expression in embryonic stem cells, focusing on Polycomb and trithorax group protein complexes. His lab is taking a multidisciplinary approach, combining biochemistry with proteomic, genomic, cell-biological, and systems biology-inspired techniques. Philipp received both his undergraduate and graduate degree in Biochemistry from Freie Universität Berlin, Germany. His PhD work focused on phosphoinositide kinase signalling pathways in lymphocytes. In 2008, he joined the laboratory of Danny Reinberg at NYU School of Medicine, New York, for his postdoctoral studies. There, he studied molecular mechanisms of Polycomb-mediated gene silencing, revealing that sister histones within single nucleosomes can carry different histone modifications in an asymmetric fashion. He moved to Edinburgh in November 2014 to start his own research group as a Sir Henry Dale Fellow and ERC Starting Grant holder.
Molecular mechanisms of epigenetic gene regulation
The overarching goal of research in our lab is to elucidate how histone modifications regulate gene expression. We are keen to understand how different histone modifiers and readers interact to establish complex regulatory systems that control development and cause disease if misregulated. We are taking a multidisciplinary approach to tackle these questions, combining biochemistry with proteomic, genomic, cell-biological, imaging-based, and systems biology-inspired techniques.
We aim to clarify how Polycomb and trithorax group proteins regulate expression of developmental genes in embryonic stem cells (ESCs). Bivalent domains harbour a distinctive histone modification signature featuring both the active histone H3 lysine 4 trimethylation (H3K4me3) mark and the repressive H3K27me3 mark. They have been suggested to maintain developmental genes in a poised state, allowing for timely expression upon differentiation while maintaining repression in ESCs. Bivalent nucleosomes adopt a previously unknown asymmetric conformation, carrying the active and repressive mark on opposite copies of histone H3. However, it has remained unclear how bivalent domains function to poise genes for expression in ESCs and whether they are essential for proper ESC differentiation and embryonic development.
To address these questions mechanistically, we performed pulldown experiments with recombinant asymmetric, bivalent nucleosomes and ESC nuclear extract (Figure 1A). We found that bivalent nucleosomes recruit repressive H3K27me3 binders but not activating H3K4me3 binders, despite the presence of H3K4me3 (Figure 1B), both in vitro and in ESCs. Moreover, we have discovered readers that specifically recognise the bivalent state, including the histone acetyltransferase complex KAT6B (MORF) and the histone variant H2A.Z chaperone complex SRCAP (Figure 1C). To determine the role of these novel bivalent binders in regulation of developmental genes, we performed knockout of KAT6B. Loss of KAT6B diminishes neuronal differentiation, indicating that bivalency-specific readers are critical for proper ESC differentiation. Our findings thus suggest a model where bivalent nucleosomes drive poising by setting up a repressed but plastic state at developmental promoters through recruitment of repressive and bivalent binders and exclusion of activators (Figure 1D). We are now testing this model by examining how repressive and bivalent readers such as PRC2 and KAT6B cooperate to maintain a repressed but plastic state in ESCs while allowing for activation of developmentally regulated genes upon differentiation.
Bryan, E., Warburton, M., Webb, K. M., McLaughlin, K. A., Spanos, C., Ambrosi, C., Major, V., Baubec, T., Rappsilber, J., & Voigt.
P. (2021). Nucleosomal Asymmetry Shapes Histone Mark Binding and Promotes Poising at Bivalent Domains. bioRxiv https://doi.
Sheahan, T. W., Major, V., Webb, K. M., Bryan, E., & Voigt, P. (2020). The TAZ2 domain of CBP/p300 directs acetylation towards H3K27 within chromatin. bioRxiv https://doi.org/10.1101/2020.07.21.214338.
Villaseñor, R., Pfaendler, R., Ambrosi, C., Butz, S., Giuliani, S., Bryan, E., Sheahan, T. W., Gable, A. L., Schmolka, N., Manzo, M., Wirz, J., Feller, C., von Mering, C., Aebersold, R., Voigt, P., & Baubec, T. (2020). ChromID identifies the protein interactome at chromatin marks. Nat. Biotechnol. 38, 728–736.
A. Outline of the nucleosome pulldown approach used to identify binding proteins of asymmetric bivalent nucleosomes.
B. H3K27me3 but not H3K4me3 readers are enriched with asymmetric bivalent nucleosomes. Additionally, novel, bivalency-specific binders are recruited (highlighted in C).
D. Model illustrating how bivalent nucleosomes support establishment of a poised state.