Timmers Group (Prof Dr Marc Timmers)
Model of the three different levels of transcription initiation control and of associated chromatin modifications (taken from Koster et al 2015 Cell 161:724).
Cancer-genome sequencing projects led to the realization that epigenetic pathways are often disturbed by gene mutations in solid cancers. The epigenetic control is exerted at the level of the structure and modification of chromatin and disturbances directly impacts tissue-specific programs of gene transcription and, hence, of cell identity and behaviour. An attractive aspect of epigenetic control for effective intervention strategies in solid cancers is the dynamic equilibrium of epigenetic states and the specificity and selectivity of the enzymes determining this equilibrium.
Epigenetic control of transcription complexes:
Our research focuses on the molecular pathways controlling methylation of lysine-4 of histone H3 (H3K4), which are frequently mutated in urothelial, lung, renal and endometrial cancers. Histone H3K4 methylation is antagonized by specific demethylases and by H3K27 methylases. All these entities are also vulnerable to mutation as shown for several solid cancers. However, the precise effects of mutational disturbances on epigenetic balances and on gene transcription are not well understood.
We investigate epigenetic balances from the viewpoints of: TGF-b/SMAD control of epigenetics in colorectal cancer, of the MLL3/4 complexes in urothelial carcinoma and of menin-MLL1/2 complexes in the MEN1 syndrome. In addition, we aim to understand the role of the KDM5 and KDM6 demethylases in setting the balances in H3K4 and H3K27 methylation and in enhancer/promoter function at a global level. Central in our research are methodologies for advanced (quantitative) proteomics, genomics and cancer cell models.
The basal transcription factor TFIID integrates both signal transduction, transcription factor activity and epigenetic signalling at the level of gene promoters to determine transcriptional frequencies. We are exploiting our knowledge of epigenetic control of gene transcription by TFIID through the development and application of small molecules targeting chromatin reader domains. These epigenetic drugs will be examined for transcriptional and cellular effects in different solid cancer models.
Future projects and goals:
- Regulation and function of histone H3K4 methylation in gene transcription programs
- Understanding the impact of oncogeneic lesions on histone methylation pathways
- Development and application of drugs targeting epigenetic pathways disturbed in solid tumors