̨Íåswag

Voigt Group

Voigt Group
Voigt Group
Philipp Voigt
Tenure Track Group Leader
Voigt Group

̨Íåswag Summary

We are interested in understanding the molecular mechanisms that control the accurate and timely expression of genes during development.

Post-translational modifications to histone proteins play key roles in these processes. We aim to understand how histone modifications or ‘marks’ set up chromatin states that support active transcription or gene repression. In particular, we are interested in the so-called bivalent domains, a peculiar combination of active and repressive histone marks found at developmentally regulated genes.

Bivalent domains are thought to keep genes in a poised state in undifferentiated cells such as embryonic stem cells, ready for activation upon signals that cause the cells to differentiate. We study how different histone modifiers and readers interact to establish complex regulatory systems that control development and cause disease if mis-regulated. We are taking a multidisciplinary approach to tackle these questions, combining biochemistry with proteomic, genomic, cell-biological, imaging-based, and systems biology-inspired techniques.

Understanding exactly how these complex regulatory systems establish proper gene expression patterns during development will allow us to investigate how these systems deteriorate during ageing and cause disease, while opening avenues towards mitigating such processes and towards applications in regenerative medicine.

Latest ̨Íåswagations

Open Access
Yuan W, Huang YC, LeBlanc C, Poulet A, De Luna Vitorino FN, Valsakumar D, Dean R, Garcia BA, van Wolfswinkel JC, Voigt P, Jacob Y Epigenetics

The oncomutation lysine 27-to-methionine in histone H3 (H3K27M) is frequently identified in tumors of patients with diffuse midline glioma-H3K27 altered (DMG-H3K27a). H3K27M inhibits the deposition of the histone mark H3K27me3, which affects the maintenance of transcriptional programs and cell identity. Cells expressing H3K27M are also characterized by defects in genome integrity, but the mechanisms linking expression of the oncohistone to DNA damage remain mostly unknown. In this study, we demonstrate that expression of H3.1K27M in the model plant Arabidopsis thaliana interferes with post-replicative chromatin maturation mediated by the H3.1K27 methyltransferases ATXR5 and ATXR6. As a result, H3.1 variants on nascent chromatin remain unmethylated at K27 (H3.1K27me0), leading to ectopic activity of TONSOKU (TSK/TONSL), which induces DNA damage and genomic alterations. Elimination of TSK activity suppresses the genome stability defects associated with H3.1K27M expression, while inactivation of specific DNA repair pathways prevents survival of H3.1K27M-expressing plants. Overall, our results suggest that H3.1K27M disrupts the chromatin-based mechanisms regulating TSK activity, which causes genomic instability and may contribute to the etiology of DMG-H3K27a.

+view abstract Nature communications, PMID: 40229276

Open Access
Bryan E, Valsakumar D, Idigo NJ, Warburton M, Webb KM, McLaughlin KA, Spanos C, Lenci S, Major V, Ambrosi C, Andrews S, Baubec T, Rappsilber J, Voigt P Epigenetics , Bioinformatics

Promoters of developmental genes in embryonic stem cells (ESCs) are marked by histone H3 lysine 4 trimethylation (H3K4me3) and H3K27me3 in an asymmetric nucleosomal conformation, with each sister histone H3 carrying only one of the two marks. These bivalent domains are thought to poise genes for timely activation upon differentiation. Here, we show that asymmetric bivalent nucleosomes recruit repressive H3K27me3 binders but fail to enrich activating H3K4me3 binders, thereby promoting a poised state. Strikingly, the bivalent mark combination further promotes recruitment of specific chromatin proteins that are not recruited by each mark individually, including the lysine acetyltransferase (KAT) complex KAT6B. Knockout of KAT6B blocks neuronal differentiation, demonstrating that KAT6B is critical for proper bivalent gene expression during ESC differentiation. These findings reveal how readout of the bivalent histone marks directly promotes a poised state at developmental genes while highlighting how nucleosomal asymmetry is critical for histone mark readout and function.

+view abstract Molecular cell, PMID: 39731917

Open Access
Wapenaar H, Clifford G, Rolls W, Pasquier M, Burdett H, Zhang Y, Deák G, Zou J, Spanos C, Taylor MRD, Mills J, Watson JA, Kumar D, Clark R, Das A, Valsakumar D, Bramham J, Voigt P, Sproul D, Wilson MD Epigenetics

DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns in vertebrates. Here we structurally and biochemically explore the interaction of DNMT3A1 with diverse modified nucleosomes indicative of different chromatin environments. A cryo-EM structure of the full-length DNMT3A1-DNMT3L complex with a H2AK119ub nucleosome reveals that the DNMT3A1 ubiquitin-dependent recruitment (UDR) motif interacts specifically with H2AK119ub and makes extensive contacts with the core nucleosome histone surface. This interaction facilitates robust DNMT3A1 binding to nucleosomes, and previously unexplained DNMT3A disease-associated mutations disrupt this interface. Furthermore, the UDR-nucleosome interaction synergises with other DNMT3A chromatin reading elements in the absence of histone ubiquitylation. H2AK119ub does not stimulate DNMT3A DNA methylation activity, as observed for the previously described H3K36me2 mark, which may explain low levels of DNA methylation on H2AK119ub marked facultative heterochromatin. This study highlights the importance of multivalent binding of DNMT3A to histone modifications and the nucleosome surface and increases our understanding of how DNMT3A1 chromatin recruitment occurs.

+view abstract EMBO reports, PMID: 39528729

Group Members

Philipp Voigt

Tenure Track Group Leader

Sofia Beltrame

Visiting Student

Megan Buckley

PhD Student

Ethan Hills

Visiting Scientist

Ben Roberts

PhD Student

Devadathan Sethumadhavan

Postdoc ̨Íåswag Scientist

Devisree Valsakumar

Postdoc ̨Íåswag Scientist

Katerina Wong

Visiting Student