Marc Timmers - Biography#

Marc Timmers graduated in Chemistry from the University of Amsterdam (BSc) and of Leiden (MSc). He was trained as a molecular biologist by dr. Titia de Lange and prof. Piet Borst (NKI, Amsterdam). He received his PhD on the mechanism of cellular transformation by adenoviral oncogenes from prof. Alex van der Eb (Leiden).

Marc Timmers started his studies on the basal transcription machinery during his post-doctoral training in biochemistry with prof. Phil Sharp (Nobel laureate 1993) at the CCR of MIT (Cambridge, USA). He continued studies towards the molecular mechanisms in eukaryotic gene expression as an independent research, which led to the molecular details of RNA polymerase II promoter opening, menin function, MEN1 and breast cancer, TBP dynamics, histone methylation in core promoter function, TFIID in pluripotency. Since 2001, Marc Timmers has been a full professor in the Center for Molecular Medicine (UMCU) affiliated with the Utrecht University. He has been a group leader in the graduate schools of Cancer, Stem cells and Development and of the Bijvoet School for Biomolecular Research in Utecht. Here, he also established teaching programs in Epigenetics and Gene Regulation and has an extended network of collaborators. Very recently, Marc Timmers has accepted the DKTK-sponsored professorship in Medical Epigenetics in Freiburg to advance the molecular understanding of epigenetic control of transcription and to exploit this to develop therapeutic modalities towards specific chromatin signalling pathways.

Research interest

My main research interest is epigenetic control of gene expression and, in particular of transcription initiation, in the context of cancer. In our studies we focus on the molecular machines responsible for ‘writing, reading and erasing’ methylation marks on histone H3 at lysine-4 (H3K4), in which we combine quantitative proteomics, genomics, biochemistry and cell biology approaches. Our current and planned activities aim at understanding protein complex assembly pathways and topologies of TFIID and histone H3K4 (de)methyltransferase complexes, their genomic distributions, dynamics of H3K4 methylation, drug interference of H3K4 and H3ac readers in cellular systems recapitulating healthy and cancerous states.

Scientific Expertise and Achievements

The research topics of the Timmers group are the molecular mechanisms of transcription initiation by RNA polymerase II (pol II) focussing on the basal transcription factors. For this we employed in vitro and in vivo techniques to study yeast and human cells. Early on we determined molecular details of open complex formation and the roles of DNA supercoiling, ATP hydrolysis, TFIIE and TFIIH. We identified an alternative TBP complex, B-TFIID, clone human BTAF1, determine the 3D structure of B-TFIID, and show that together with NC2 it controls chromatin dynamics of TBP. We identified all subunits of the human CCR4-NOT complex and discovered its E3 ubiquitin ligase activity. Our quantitative proteomics showed that TFIID is the major binder for H3K4me3-marked nucleosomes. We determined molecular structure and interactions of the TAF3 PHD with H3K4me3. We found that in embryonic stem cells H3K4 methylation states are dynamically controlled. We identified the menin tumor suppressor as an adaptor for nuclear receptors activating transcription by recruiting H3K4 histone methyltransferase complexes. This motivated our epidemiology studies on MEN1 patient cohorts to find that MEN1 is a breast cancer susceptibility gene. This sparked the implementation of early breast cancer detection in MEN1 patients.