Research Focus

Haematopoietic stem cells (HSCs) are able to generate all cell types of the haematopoietic system, but at the same time have the ability of self-renewal. In the course of life, HSCs lose the ability to self-renew and also show a reduced potential for differentiation in cells of the adaptive immune system. Cellular stress as well as repeated activation of the HSCs by infections play a decisive role. However, the molecular causes for these age-related changes are not yet fully understood.

In our group we were able to show that the inactivation of the transcription factor Myc-interacting zinc finger protein 1 (Miz-1) accelerates these aging processes. Through gene expression analyses and investigations of epigenetic changes, we hope to gain new insights into the molecular causes of the ageing of HSCs. These investigations should contribute to understanding the age-related loss of function of HSCs.

Sepsis is a life-threatening organ failure caused, among other things, by a misdirected systemic immune reaction of the host in response to infections. Sepsis is currently the most common cause of death in intensive care units worldwide. The immune system reacts to a bacterial infection with an increased release of cytokines. The ratio of pro- and anti-inflammatory cytokines plays an important role in the development of sepsis. In the course of a sepsis/infection, the cell count of both the innate and the adaptive immune system falls sharply. This is caused by an increased cell death (apoptosis) of the immune cells. As a result, the production of cells of the innate immune system (myeloid cells) increases and the amount of cells of the adaptive immune system (lymphocytes) decreases, similar to age-related changes.

To ensure this, HSCs enter the cell cycle and produce effector cells; how this is regulated and to what extent this is responsible for the development of sepsis or its late consequences is largely unknown.

The aim of our research is to investigate the effect of sepsis on the function of hematopoietic stem cells. A particular focus is on epigenetic alterations and whether these affect the functionality of HSCs or the resulting effector cells.

Many factors that are involved in the development and differentiation of haematopoietic cells can lead to the development of tumours as a result of defective regulation; during this process transcription factors play an important role. The transcription factor c-Myc is strongly overrepresented in many human tumours due to chromosomal translocations. An increased c-Myc level leads to a fatal misregulation of cellular processes such as altered metabolism, increased proliferation, cell growth and activated signalling pathways. By using the "Eµ-Myc" transgenic mouse model, which resembles the genetic cause of Burkitt's lymphoma, we can investigate the molecular causes of lymphoma formation. One focus is on novel pharmacological and genetic concepts to interfere with the function of c-Myc. Our research projects include:

• Characterization of changes during malignant transformation on the transcriptional level
• Studies on the interaction of the transcription factors Miz-1 and c-Myc in B-cells and lymphomas
• Use of histone deacetylase inhibitors (HDACi) in the treatment of lymphomas

Our research results should provide new, mechanistic insights into tumor development and contribute to a deeper understanding of the complex function of transcription factors. In addition, potential molecular targets for cancer therapy will be identified.

Multicellular organisms are exposed to different types of stress on a daily basis, which can lead to damage as well as diseases such as cancer. To avoid this, organisms can react in different ways to stress, such as DNA damage or infections. For example, DNA damage in cells can trigger various processes, including cell cycle arrest and repair or apoptosis. Recent studies have shown that sensors for DNA damage (such as ATM) can also influence an immune response. It has been shown that low levels of DNA damage increase the chances of survival of septic mice by inducing autophagy. Furthermore, it could be shown that sensors for DNA damage also induce the expression of pro-inflammatory cytokines and activation of the NF-kB signalling pathway.

The transcription factor Miz-1 can regulate the cellular response to DNA damage by regulating the activation of the apoptosis-induced target genes of the tumor suppressor p53 and thus controlling the cellular stress response. It was also shown that Miz-1 inhibits the expression of the pro-inflammatory factor C/EBPδ and that without Miz-1 the pro-inflammatory immune response is excessively activated.

Our research focuses on molecular mechanisms that link the activation of immune cells and the cellular stress response.

The adaptive immune system loses effectiveness significantly during aging. A gradual deterioration of the adaptive immune system - often described as immunosenescence - is fundamental for the declining immune response and leads to an increased susceptibility to inflammations, infections, autoimmune diseases or malignant tumors with age. Using a B-cell-specific knock-out of the transcription factor Myc-interacting zinc finger protein 1 (Miz-1), we found that Miz-1 is essential for B-cell homeostasis and immune competence. Deletion of Miz-1 leads to similar effects as premature B-cell ageing. Using this model system it is possible to investigate the molecular mechanisms of immunological ageing and the impairment of the immune response.

Our work focuses on the cause of the reduced effectiveness of B-cells and the secondary immune response, the response to systemic infections and the role of the intestinal flora in the function of the immune system in aging.

The conditional inactivation of Miz-1 in early T cell development leads to an almost complete loss of the T cell population. To investigate the function of Miz-1 in T cell activation and adaptive stress response, Miz-1 was specifically inactivated in mature T cells. It was shown that Miz-1-deficient T-cells show a phenotype that can otherwise only be detected in aging, suggesting a role of Miz-1 in T-cell maturation.

We want to investigate the role of Miz-1 in T cell activation and immune response. In addition to cytokine production, the DNA damage response will also be investigated.

Colorectal cancer is one of the world's leading causes of death, and tumor incidence increases with age and an unhealthy lifestyle. It has shown an important role of the Wnt pathway in the development of colorectal cancer, most often as a result of mutations in the Wnt pathway leading to increased activity. The proto-oncogene Myc is an important target gene of the Wnt/β catenin signalling pathway and the constitutive expression of Myc is often associated with poor prognosis in many cancers.

We and others have shown that Miz-1 is crucial for Myc-induced tumor development. Here Miz-1 represses the expression of the negative cell cycle regulators P21^Cip1 and P15^Ink4b. In addition, Miz-1 regulates the cellular p53 response and counteracts p53-induced apoptosis, which is crucial to prevent the development of cancer. This mechanism depends on the interaction of Miz-1 and Myc. Furthermore, cytoplasmic Miz-1, independent of Myc, controls the Wnt signalling pathway by protecting dishevelled (Dvl), by Dapper1 (Dpr1) mediated degradation, and thus promotes cell proliferation. In addition, Miz-1 has been shown to be a direct activator of Wnt inhibitory factor 1 (WIF-1).

Miz-1 plays a multiple role in the Wnt signalling pathway and is therefore an interesting candidate for investigations into the molecular mechanisms involved in the development of colorectal cancer.