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Philipp Voigt

Co-workers:

Elana Bryan, Thomas Sheahan, Marie Warburton, Kim Webb

Molecular Mechanisms of Epigenetic Gene Regulation

The genetic information  of eukaryotic organisms is packaged into chromatin, a complex assembly of DNA, RNA, and proteins. The basic unit of chromatin is the nucleosome, which is formed by DNA wrapping around a histone octamer. Histones not only constitute the structural backbone of chromatin but also provide ample opportunity for regulating  gene expression. They undergo a host  of posttranslational modifications, which are thought to impact transcription either by directly modulating chromatin structure or by recruiting effector proteins. The overarching goal of research in our lab is to determine the mechanistic intricacies of histone modifications. Moreover, we aim to understand how different systems of chromatin modifiers interact to regulate and fine-tune gene expression.

In particular, we are interested in the repressive histone modification histone H3 lysine 27 trimethylation (H3K27me3), which is placed by Polycomb Repressive Complex 2 (PRC2). Despite the well-established role of PRC2 and H3K27me3 during development, it remains unclear exactly how this modification functions to repress genes in mechanistic terms. Paradoxically, in embryonic stem cells, H3K27me3 is found at promoters of developmental genes alongside the active mark H3K4me3, which is catalysed by members of the SET1 and MLL methyltransferases (Figure 1A). The resulting bivalent domains are presumed to poise developmental genes for activation, facilitating rapid and robust expression upon appropriate differentiation cues while keeping them repressed in embryonic stem cells. However, direct evidence for this concept remains largely elusive.

Our previous work shed light on the conformation  and establishment of bivalent domains, demonstrating that bivalent nucleosomes are in an asymmetric conformation, carrying H3K27me3 and H3K4me3 on different copies of histone H3 within single nucleosomes (illustrated in Figure 1). However, it remains unclear how the bivalent marks are decoded  and how bivalency contributes to gene activation and plasticity  during differentiation. We are currently addressing these questions by employing biochemical and cell-biological approaches. In addition, we are aiming to establish quantitative, systems biology- inspired approaches to define the physiological functions of bivalent domains. Specifically,  we are testing the hypothesis that bivalency may represent a dynamic equilibrium between active and repressive factors that ensures proper timing of developmental gene expression (Figure 1B). As both temporal and spatial accuracy of expression patterns is essential for development, bivalency may be indispensable to proper embryonic development.

 

We are currently seeking enthusiastic, highly motivated, and creative postdoctoral researchers to join our lab. Please contact Philipp Voigt (philipp.voigt@ed.ac.uk) for more information.

Selected publications:

Bonasio, R., Lecona, E., Narendra, V., Voigt, P., Parisi, F., Kluger, Y., and Reinberg, D. (2014). Interactions with RNA direct the Polycomb group protein SCML2 to chromatin where it represses target genes. eLife 2014;3, e02637.

Voigt, P., Tee, W.-W., and Reinberg, D. (2013). A double take on bivalentpromoters. Genes Dev. 27, 1318–1338. 38
 
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. Interactions between active and repressive factors control the establishment of bivalent domains in embryonic stem cells.

B. As their key function, bivalent domains may ensure proper timing of expression of developmental genes.