DKTK - Timmers LabDepartment of Urology ZKF

Prof. Dr. Marc Timmers

Our group studies transcriptional regulation in relation to chromatin modifications which are relevant to human diseases like cancer and neurodegeneration. Epigenetic control is exerted at the level of the structure and modification of chromatin and disturbances directly impact tissue-specific programs of gene transcription and, hence, of cell identity and behaviour. An attractive aspect of epigenetic control for effective intervention strategies in cancers is the dynamic equilibrium between epigenetic states and the specificity and selectivity of the enzymes determining this equilibrium. Bladder cancer is a prime example of a disease associated with genetic mutations in key epigenetic regulators (UTX/KDM6A, MLL4/KMT2D, MLL3/KMT2C, ARID1A, EP300 and CBP). This type of tumour is characterized by a strong gender imbalance towards men.

In particular, we focus on the six MLL complexes which deposit histone H3K4 methylation and regulate the activity of gene enhancers and gene promoters. In recent work, we found that the gene-specific transcription factor JUNB forms a feed-forward loop with the epigenetic regulator MLL4, which is essential for the activation of TGF-b target genes (PMID: 42031562). The menin subunit of the MLL1/MLL2 complexes has become a major focus for leukemia research as chemical menin-MLL inhibitors display remarkable efficacy in certain types of AML. Two have already received FDA approval (ruvemenib and ziftomenib) for treatment of MLLr- and NPM1-AMLs with several still in clinical trials (a.o. BMS-986158). In recent work with the group of Prof. Robert Zeiser, we examined transcription factor JUND and its targets as candidates for combination therapies with menin-MLL inhibitors (PMID: 41144759).

All cellular and epigenetic signaling culminates in the loading of RNA polymerase II to specific sets of gene promoters. The basal transcription factor TFIID plays a coordinating role in setting transcription initiation frequencies. We are examining the chromatin aspects on the dynamic regulation of TFIID activity to find that the PHD finger of the TAF3 subunit is a unique reader of a novel chromatin modification, serotonylation of H3Q5 (PMID: 40637225).

Besides mechanistic studies, we are performing both genetic and chemical screens to determine targetable vulnerabilities of bladder cancer cell lines and primary 2D and 3D cultures from bladder cancers with the aim to develop new treatment options for this disease. For this, we constructed a custom-made library of 600 high-quality chemical compounds targeting epigenetic regulators. This FREpi library was designed in collaboration with Prof. Manfred Jung. We published its first use in a high-content automated microscopy screen, which identified the BRD4 transcriptional regulator as a key component for transcriptional repression of the TAF1 gene underlying the neurodegenerative disorder X-linked dystonia-parkinsonism, XDP (PMID: 42086561). This laid the basis for our on-going investigations of the molecular mechanism of BRD4 action and strategies for long-term interference in XDP pathology.

In general, our studies of gene transcription and chromatin regulation employ cell and organoid models for cancer and neurodevelopment, molecular biology, proteomics, genomics, live-cell imaging, automated microscopy and bioinformatics approaches.

Future projects and goals

Regulation and function of histone H3K4 methylation in gene transcription programs

Understanding the impact of oncogenic lesions on histone methylation pathways

Development and application of drugs targeting epigenetic pathways disturbed in solid tumours

Molecular mechanism underlying X-linked dystonia-parkinsonism for therapeutic interference

FREpi Library

Interested in contributing to our research?

Motivated and ambitious researchers at all levels (M.Sc. and Ph.D. students, post-doctoral fellows) are encouraged to contact us (m.timmers -at- dkfz-heidelberg.de or baerbel.hansen -at- dkfz-heidelberg.de) for open positions.