- Manipulation of host chromatin by Kaposi sarcoma-associated herpesvirus (Prof. Grundhoff, HPI), 1 Postdoc
Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of several human tumors, including Kaposi sarcoma (KS) and primary effusion lymphoma (PEL). Together with the related Epstein Barr virus (EBV), KSHV is estimated to cause more than 200.000 cancer cases per year, accounting for almost 2% of the worldwide tumor burden. Like other herpesviruses, KSHV has the ability to establish latency (a stage of the viral lifecycle during which the viral genome can persist as a nuclear episome for virtually indefinite periods of time) in its target cells. While it is thought that viral tumorigenesis represents a long-term consequence of latent infection, the molecular events which lead to cellular transformation are poorly understood. We have previously demonstrated that, upon latency establishment, KSHV subverts epigenetic host cell pathways to recruit polycomb repressor complexes and restrict viral gene expression. The goal of this project is to investigate the impact of such manipulations on host chromatin. Using relevant in vitro models of viral latency, the project will employ state-of-the art genomic analysis tools to study short and long-term consequences for epigenetic and transcriptional regulation of host cell chromatin. We expect that the project will not only shed light on general mechanisms that permit latency establishment, but will also further our understanding of KSHV-mediated oncogenesis.
- Epigenetic changes induced by tumorigenic and non-tumorigenic polyomaviruses (Prof. Fischer, UKE). 1 PhD student
Polyomaviruses (PyV) are highly prevalent viruses found in every species. Up to date we know 13 human PyV which cause a lifelong persistent infection of their host. Only few are clinically relevant inducing severe clinical symptoms under immune suppression. Mostly, these diseases are a consequence of viral reactivation and massive viral replication. There is only one human polyomavirus, the Merkel cell polyomavirus (MCPyV), which under immune suppression is involved in tumor formation. Within the tumor, the viral DNA is integrated into the host cell genome and viral replication is abrogated due to mutations within the early viral gene region. PyVs encode for early viral gene products, the large and small tumor antigens, which de-regulate the cell cycle and can induce cellular transformation under in vitro conditions. Within EPILOG we will address the following questions: Do early viral gene products induce chromatin changes of the host cell genome? Do early gene products of tumorigenic and non-tumorigenic polyomaviruses differ in this function? Do these chromatin changes persist – also after clearance of the viral infection? Are these changes associated with pathogeneses?
- Epigenetic Imprinting as a basis for virus-mediated oncogenesis: Hit-and-Run Transformation (Prof. Dobner, HPI). 1 PhD student
Work in this project aims at elucidating molecular mechanisms underlying virus-mediated transformation processes. Towards this goal we use human adenovirus (HAdV) as model to study the molecular interactions involved in viral carcinogenesis. Studies will employ an integrated experimental approach that combines different cell transformation models, including primary mammalian cells, humanized mice and adult human stem cells with genome-wide analytical methods to investigate epigenetic changes of the host genome induced as a consequence of HAdV oncogene expression. These basic studies not only provide valuable information into the role of persistent host chromatin changes during to virus-mediated oncogenesis but may also provide further support for the Hit-and-Run hypothesis that imprinted alterations of the host epigenome is a general mechanism that contributes to the etiology of infection-associated cancers.
- Study of HBV-induced epigenetic modifications and long term consequences on the host chromatin of human hepatocytes. (Prof. Dandri, UKE). 1 PhD student
Hepatitis B virus (HBV) infection causes chronic hepatitis, liver cirrhosis, and is strongly associated with the development of hepatocellular carcinoma (HCC). HBV-mediated epigenetic alterations have been observed in vitro and are commonly found in HBV-related HCCs. In this regard, expression of the regulatory viral protein HBx was shown to promote aberrant DNA hypermethylation in host genes involved in tumor suppression, cell cycle, immune escape, apoptosis and metabolism. Because of the limited availability of HBV-infection models, little is known about the dynamic of epigenetic modifications in the course of infection, whether these are permanently induced, which host genes are mostly targeted and their pathogenic consequences. By employing human liver chimeric mice and taking advantage of the innovative tools available within the consortium, we plan to determine whether epigenetic changes occur early upon HBV infection and are associated with specific changes of the host chromatin, as well as whether such epigenetic aberrations persist and can even be maintained in human cells that cleared the infection through cell division.
- Yersinia induced immune modulation of human macrophages (Prof. Aepfelbacher, UKE). 1 PhD student
Enteropathogenic Yersinia enterocolitica induce a sustained reorientation of the cytokine profile in human macrophages. It is well known that Yersinia modulates the function of immune cells through effector proteins that they inject into the cells via their type three secretion system (T3S). One of these effectors even enters the nucleus and modifies the activity of kinases like PKN/PRK and RSK, as well as interleukin-10 expression and Jak/Stat signalling. The specific type of lipopolysaccharide produced by Yersinia and the pore complex of the T3S also have a profound and sustained impact on the gene expression profile of immune cells. Interestingly, many of the biochemical activities stimulated by the bacteria in macrophages have been implicated in epigenetic chromatin modifications. We therefore investigate whether Yersinia induces epigenetic histone- or DNA modifications in human macrophages and which bacterial virulence factors may be involved. These investigations will help us to find out whether a specific bacterial infection also produces a specific epigenetic imprint in immune cells and how the bacteria profit from modifiying the epigenome of cells during infection.
- Effects of virus infection on local and systemic histone- and DNA modifications (Prof. Kehr, UHH). 1 PhD student
Plants are regularly exposed to stress conditions in their natural environment. When plants repeatedly perceive potentially harmful factors like pathogens or abiotic stress, they often react with increased defense readiness. This is operative against future stress conditions in the life of the plant itself, but can also prime future generations. The exposure to pathogens like viruses often leads to increased tolerance or immunity against a broad range of infections. This is not restricted to the site of infection, but can also protect distant parts of the plant (systemic acquired resistance). The ability of plants to adapt to abiotic stress or pathogens within a few generations cannot be explained by incidental mutations and subsequent selection. The exact molecular mechanisms of this adaptation are as yet unknown. It is assumed that epigenetic regulatory mechanisms like cytosine and histone methylation and histone (de)acetylation are involved in this fast adjustment. Such epigenetic modifications of chromatin allow long-term adaptation, since they can be transmitted during mitosis and meiosis.
- Differences in histone modification and gene expression in plants after autoactivation or bacterially induced changes of the immune response (Prof. Hoth, UHH). 1 PhD student
Plants are frequently challenged by pathogens and are for defense purposes equipped with a highly effective innate immune system that relies on the specific recognition of pathogen-associated molecular patterns by pattern recognition receptors in the plasma membrane and of effectors, which are secreted by microbes into plant cells, by cytosolic NLR (Nod-like receptors) immune receptors. The plant NLRs are conserved and act highly similar to animal and human NLRs. Pathogen-induced signaling leads to the activation of defense genes that are normally silent. Defense gene activation is regulated through histone modification and DNA methylation. Recently, it was suggested that chromatin changes determine memory effects in immunity. Within EPILOG we will address the following questions: Which histon modifications that are established during autoimmunity and/or after bacterial infection contribute to epigenetic memory? What is the nature of the genes regulated through these histon modifications? Can we follow histon modifications on the single cell level?