Epigenetic changes are among the earliest events in tumor development. These changes are thought to lead to transient deregulations of genomes, which are then permanently altered by mutations, structural rearrangements and copy number variations, leading to a general phenotype of genomic instability. Several large-scale sequencing studies, including our own, have identified mutations involving chromatin modifiers as one of the most common genomic alterations in cancer (Timmermann et al. 2010, Kerick et al. 2011, Grasse et al. 2018). However, their influence on the epigenome and their effects on cellular proliferation are only marginally known and are the focus of our work.
Three main areas of interest have developed in recent years:
Core topics of our research
Core topic 1: Function of Satellite III non-coding RNA (SATIII):
In this topic we deal with questions concerning a non-coding and repetitive RNA, the satellite III RNA (SATIII). Repetitive regions of DNA are generally de-methylated and thus activated early and extensively during tumorigenesis. The activation of SATIII RNA plays an important role in the stress response.
This raises the following questions:
How and when is SATIII RNA expressed? How is it regulated? What is its function in the heat stress response? How are nuclear stress bodies formed? How does it influence tumor progression and resistance to therapy - especially in HPV-associated head and neck squamous carcinoma (HNSCC) and lung tumors? Can we block it through targeted and tissue-specific therapy and thus influence the pathogenesis of the tumors?
Core topic 2: Mutations in the histone acetyltransferase (HAT) CREBBP.
Our genome-wide data sets of tumors have shown that epigenetic modifiers are most frequently affected by mutations and genetic restructuring. This raises the question of what influence these changes have on tumor development - and growth. We focus in particular on the histone acetyltransferase CREBBP (CBP) and ask:
Why do certain hotspot mutations occur frequently in tumors, especially in small cell lung tumors? How does the mechanism change and which signaling pathways are affected? Can a targeted therapy be used in these patients?
Core topic 3: Changes in the splicing process
The diversity of the genome is due to the large number of different genes, but also to the different transcript isoforms that are formed by these genes. Transcript isoforms are produced by different splicing processes, which are often disrupted in malignant processes. For example, mutations in the splicing factor SF3B1 are found in 20% of all patients with myelodysplastic syndrome (MDS). Other tumors are also affected by mutations in this gene: 15% of all chronic lymphocytic leukemias (CLL) or 4% of all melanomas. Breast (2%) - pancreas (2%) - lung (2%) - and prostate (1%) tumors are also affected. This raises the following questions, among others:
Why are splicing factors very frequently mutated in tumors? What changes occur in CLL and MDS with mutations in the splicing factor SF3B1? Why are these mutations (in addition to mutations in the tumor suppressor TP53) associated with a poor prognosis for patients?
