Chromatin and Ageing

Chromatin is the complex of DNA and proteins that can be found in the nucleus of a cell. We are very interested in understanding how the architecture of chromatin can regulate gene expression. In particular, we aim to elucidate how age-related changes in the epigenome influence transcriptional outputs and ultimately, cellular fate decisions. Over the recent years, we became fascinated by the connection of other cellular pathways with epigenetic mechanisms and have expanded our research to address the connection between metabolism and inter-organellar communication on chromatin architecture. To this end we combine mechanistic approaches in S. cerevisiae and established cell culture systems with analysis of primary cells and tissues using biochemistry, cell biology and a variety of state-of-the art deep sequencing technologies.

Selected projects

Chromatin-mediated regulation of gene expression

Wir haben kürzlich eine Histonmodifikation (Glutamin-Methylierung von Histon H2A an Glutamin 105) identifiziert, die ausschließlich mit der Funktion der RNA-Polymerase I verbunden ist. Diese Modifikation reguliert die Zugänglichkeit der rDNA, indem sie die Bindung des Histon-Chaperons FACT hemmt, was zu einem verminderten Einbau von H2A in den rDNA-Locus führt (Tessarz et al., 2014). Anknüpfend an diese Arbeit identifizierten wir spezifische Proteine, welche diese Modifikation auslesen und mit der Ribosomen-Assemblierung, der rRNA-Prozessierung und der Erkennung von Stoffwechselzuständen verbunden sind. Interessanterweise hängt die Methylierung von H2AQ105me von einer anderen Histonmodifikation ab, der Acetylierung von Lysin 56 in Histon H3, einer Modifikation, die - neben anderen - mit der rRNA-Transkription in Verbindung gebracht wurde. Dieser Forschungsstrang führte auch zur Identifizierung eines sehr interessanten zellulären Crosstalks. Mutationen in H3K56 führen zu Veränderungen in der naszierenden RNA-Transkription, während die RNA-Spiegel im Steady-State nahezu unbeeinflusst bleiben. Durch einen genomweiten Screen nach genetischen Interaktoren von H3K56A identifizierten wir das RNA-bindende Protein Puf5. Wir konnten zeigen, dass Puf5 Transkripte kontextabhängig entweder stabilisieren oder abbauen kann und die regulären mRNA-Spiegel aufrechterhält, indem es die Chromatin-vermittelte Regulation der naszierenden Transkription mit mRNA-Abbauwegen verbindet (Kochan et al., 2020). Neben unserer Arbeit zur Histonmodifikation und ihrer Rolle bei der Regulation der Genexpression sind wir auch sehr daran interessiert zu verstehen, wie die Chromatinarchitektur die Transkription direkt regulieren kann. Ein Beispiel ist unsere Arbeit über das Histon-Chaperon FACT und wie es den Zugang zu Promotoren reguliert. In embryonalen ES-Zellen hemmt FACT die Antisense-Transkription, indem es das Nukleosom -1 aufrechterhält und damit den Zugang zum Promotor einschränkt (Mylonas et al., 2018).  Derzeit erweitern wir diese Arbeit, um zu verstehen, wie Chromatinarchitektur und Transkriptionsregulation im Kontext der Alterung zusammenhängen.

Connection of metabolism and the epigenome

Central metabolites, such as acetyl-CoA, S-adenosylmethionine or the NAD/NADH ratio are intimately linked with epigenetic reactions as they serve as substrates or co-factors for enzymes modifying histones and DNA. Conversely, the induction or repression of metabolic enzymes is under epigenetic control. As ageing is associated with changes in both, metabolism and the epigenome, we are very interested in understanding how the connection between these two essential cellular pathways is impacted. We use mesenchymal stem cells (MSCs) derived from the endosteum of mice to study this interplay. MSCs are important to maintain integrity of bone, but are also essential for haematopoiesis and thus, play a critcal role during the ageing process. From previous work we know that MSCs can differentiate into chondrocytes, osteoblasts and adipocytes to regenerate bone, cartilage and fat in the bone. However, with age, this differentiation is skewed towards the adipogenic lineage. We could demonstrate that these defects in osteogenesis originate from age-associated changes in the chromatin landscape, due to changes in the histone acetylation states in aged MSCs (Pouikli et al., 2020). This change in histone acetylation is a consequence of impaired acetyl-CoA export from mitochondria to the cytoplasm due to lower levels of the carrier (CiC) responsible for this reaction. We uncovered that the decrease in CiC depends on an increase in mitochondrial quality control mechanisms that lead to higher turnover rate of the carrier in aged cells. Strikingly, circumventing acetyl-CoA export by medium supplementation with acetate rescues histone acetylation and osteogenic differentiation capacity of aged MSCs, placing the metabolism-epigenetic interplay at the heart of the differentiation changes. Together with work from other labs, this demonstrates that interventions on the epigenetic level might be a way for cellular rejuvenation.

Epigenetic heterogeneity

One feature of ageing is an increase in biological noise in many tissues. To study this on the level of chromatin and to understand if all cells in our tissues are impacted in the same way, we employ single-cell epigenomic mapping. In addition, we are very interested in understanding if the potential noise can be maintained in in vitro systems. To study this potential phenomenon of epigenetic memory we use organoid systems that we setup directly from aged tissue.

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