Voigt Group

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

Research 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 Publications

Dias Mirandela M, Zoch A, Leismann J, Webb S, Berrens RV, Valsakumar D, Kabayama Y, Auchynnikava T, Schito M, Chowdhury T, MacLeod D, Xiang X, Zou J, Rappsilber J, Allshire RC, Voigt P, Cook AG, Barau J, O'Carroll D Epigenetics

The PIWI-interacting RNA (piRNA) pathway guides the DNA methylation of young, active transposons during germline development in male mice. piRNAs tether the PIWI protein MIWI2 (PIWIL4) to the nascent transposon transcript, resulting in DNA methylation through SPOCD1 (refs. ). Transposon methylation requires great precision: every copy needs to be methylated but off-target methylation must be avoided. However, the underlying mechanisms that ensure this precision remain unknown. Here, we show that SPOCD1 interacts directly with SPIN1 (SPINDLIN1), a chromatin reader that primarily binds to H3K4me3-K9me3 (ref. ). The prevailing assumption is that all the molecular events required for piRNA-directed DNA methylation occur after the engagement of MIWI2. We find that SPIN1 expression precedes that of both SPOCD1 and MIWI2. Furthermore, we demonstrate that young LINE1 copies, but not old ones, are marked by H3K4me3, H3K9me3 and SPIN1 before the initiation of piRNA-directed DNA methylation. We generated a Spocd1 separation-of-function allele in the mouse that encodes a SPOCD1 variant that no longer interacts with SPIN1. We found that the interaction between SPOCD1 and SPIN1 is essential for spermatogenesis and piRNA-directed DNA methylation of young LINE1 elements. We propose that piRNA-directed LINE1 DNA methylation requires a developmentally timed two-factor authentication process. The first authentication is the recruitment of SPIN1-SPOCD1 to the young LINE1 promoter, and the second is MIWI2 engagement with the nascent transcript. In summary, independent authentication events underpin the precision of piRNA-directed LINE1 DNA methylation.

+view abstract Nature, PMID: 39294378

Valsakumar D, Voigt P Epigenetics

Nucleosomes constitute the fundamental building blocks of chromatin. They are comprised of DNA wrapped around a histone octamer formed of two copies each of the four core histones H2A, H2B, H3, and H4. Nucleosomal histones undergo a plethora of posttranslational modifications that regulate gene expression and other chromatin-templated processes by altering chromatin structure or by recruiting effector proteins. Given their symmetric arrangement, the sister histones within a nucleosome have commonly been considered to be equivalent and to carry the same modifications. However, it is now clear that nucleosomes can exhibit asymmetry, combining differentially modified sister histones or different variants of the same histone within a single nucleosome. Enabled by the development of novel tools that allow generating asymmetrically modified nucleosomes, recent biochemical and cell-based studies have begun to shed light on the origins and functional consequences of nucleosomal asymmetry. These studies indicate that nucleosomal asymmetry represents a novel regulatory mechanism in the establishment and functional readout of chromatin states. Asymmetry expands the combinatorial space available for setting up complex sets of histone marks at individual nucleosomes, regulating multivalent interactions with histone modifiers and readers. The resulting functional consequences of asymmetry regulate transcription, poising of developmental gene expression by bivalent chromatin, and the mechanisms by which oncohistones deregulate chromatin states in cancer. Here, we review recent progress and current challenges in uncovering the mechanisms and biological functions of nucleosomal asymmetry.

+view abstract Biochemical Society transactions, PMID: 38778762

Agostinho de Sousa J, Wong CW, Dunkel I, Owens T, Voigt P, Hodgson A, Baker D, Schulz EG, Reik W, Smith A, Rostovskaya M, von Meyenn F Epigenetics

Human pluripotent stem cells (hPSCs) are of fundamental relevance in regenerative medicine. Naïve hPSCs hold promise to overcome some of the limitations of conventional (primed) hPSCs, including recurrent epigenetic anomalies. Naïve-to-primed transition (capacitation) follows transcriptional dynamics of human embryonic epiblast and is necessary for somatic differentiation from naïve hPSCs. We found that capacitated hPSCs are transcriptionally closer to postimplantation epiblast than conventional hPSCs. This prompted us to comprehensively study epigenetic and related transcriptional changes during capacitation. Our results show that CpG islands, gene regulatory elements, and retrotransposons are hotspots of epigenetic dynamics during capacitation and indicate possible distinct roles of specific epigenetic modifications in gene expression control between naïve and primed hPSCs. Unexpectedly, PRC2 activity appeared to be dispensable for the capacitation. We find that capacitated hPSCs acquire an epigenetic state similar to conventional hPSCs. Significantly, however, the X chromosome erosion frequently observed in conventional female hPSCs is reversed by resetting and subsequent capacitation.

+view abstract Science advances, PMID: 37774033

Group Members

Philipp Voigt

Tenure Track Group Leader

Megan Buckley

PhD Student

Ethan Hills

Visiting Student

Ben Roberts

PhD Student

Devadathan Sethumadhavan

Postdoc Research Scientist

Devisree Valsakumar

Postdoc Research Scientist

Katerina Wong

Visiting Student