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 affect disease states. We are taking a multidisciplinary approach to tackle these questions, combining biochemistry with proteomic, genomic, cell-biological, imaging-based, and systems biology-inspired techniques.
Our current focus is on the interplay between Polycomb and Trithorax group proteins at bivalent domains and poised enhancers, and we aim to clarify how these complexes 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 remains unclear how bivalent domains function to poise genes for expression in ESCs and whether they are essential for proper ESC differentiation and development.
To address these questions mechanistically, we performed pulldown experiments with ES cell nuclear extract and recombinant asymmetric, bivalent nucleosomes (Figure 1A). We found that bivalent nucleosomes are unable to recruit binding proteins for H3K4me3, despite presence of the mark (Figure 1B), both in vitro and in ESCs (as determined by ChIP). In contrast, bivalent nucleosomes retain binding of H3K27me3 binders. Moreover, we further found that the bivalent mark combination attracts chromatin proteins that are not recruited by each mark individually (Figure 1C), among them the histone acetyltransferase complex KAT6B (MORF) and the histone H2A.Z chaperone complex SRCAP. Knockout of KAT6B diminishes neuronal differentiation, showing that bivalency-specific readers are critical for proper ESC differentiation. Our findings reveal how histone mark bivalency directly promotes establishment of a poised chromatin state at developmental genes. They suggest a model by which bivalent nucleosomes mediate poising by preventing binding of activating factors while being bound by Polycomb complexes and bivalency-specific binding proteins (Figure 1D). We are now testing this model by determining the mechanisms by which PRC2 and KAT6B regulate gene expression and how their functions interface with other modifications found at bivalent promoters, aiming to extend the current definition of bivalency
Skourti-Stathaki, K., Torlai Triglia, E., Warburton, M., Voigt, P., Bird, A., & Pombo, A. (2019). R-Loops Enhance Polycomb Repression at a Subset of Developmental Regulator Genes. Mol. Cell 73, 930–945.
Jacob, Y., and Voigt, P. (2018). In vitro assays to measure histone methyltransferase activity using different chromatin substrates. Methods Mol. Biol. 1675, 345–360.
Voigt, P., Leroy, G., Drury, W.J., Zee, B.M., Son, J., Beck, D.B., Young, N.L., Garcia, B.A., and Reinberg, D. (2012). Asymmetrically Modified Nucleosomes. Cell 151, 181–193.
A. Outline of the nucleosome pulldown approach employed to determine binding proteins of asymmetric bivalent nucleosomes.
B. H3K27me3 but not H3K4me3 binding proteins are enriched on 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.