Timmers Group

 

Marc Timmers: Chromatin & Transcription

Picture of groupleader Prof. Marc Timmers

H.T. Marc Timmers
Tel.: +31 (0)88 75 68981
E-mail: H.T.M.Timmers -at- umcutrecht.nl

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The Timmers Laboratory
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Synopsis

Proper regulation of mRNA synthesis lies at the heart of cellular processes like cell proliferation and differentiation in eukaryotes. The research focus of the Timmers lab is to understand the molecular mechanisms of the interplay between chromatin modifications (in particular, histone methylation) and basal transcription factors like TFIID. We employ and maintain "state-of-the-art" proteomics and genomics technologies to study the dynamics and genome localization of transcription factor complexes upon internal and external cues.

 

Transcription and chromatin

The RNA polymerase II (pol II) system in the eukaryotic nucleus is under control of a variety of checks and balances. These involve signal transduction pathways, DNA-sequence specific activators, transcription co-factors and chromatin remodelling machines. Central in this is access of the basal transcription machinery to the core promoter of pol II-dependent genes. Together, this results in a transcriptional state, which is highly dynamic and can adjusted rapidly to the cells' need. A particular core promoter is subjected to different regulatory inputs and the challenge is to understand their contribution to the transcriptional output.

 

Structural model for the B-TFIID complex based on 3D reconstruction of negative-stained electron microscopic images. This work was performed with the group of dr. Patrick Schultz at the IGBMC. Histone methylation patterns In vivo and in vitro dynamics of TFIID complexes Global interaction map of the ubiquitin pathway Interplay nuclear receptors and histone methylation.

Chromatin modification plays an important role in regulating access of pol II and marking genes for expression. Many different modifications have been identified on the core histones, which together form the "histone code". Histone methylation is particularly interesting as it can both mark active and inactive promoters. In addition, methylation can regulated by the ubiquitylation of histones. The challenge to the field is to understand how a combination of histone modifications (methylation, phosporylation and acetylation) contributes to cellular decisions of activation or repression of gene activity.

Our recent highlight is the discovery of anchoring of the TFIID transcription factor to nucleosomes carrying the activating H3K4me3 mark. Besides "reading" we investigate the "writing" of this mark, which involves oncogenic factors like menin and the MLL (Mixed-Lineage Leukemia) proteins. We found that transcription activation by nuclear receptor proteins like the estrogen receptor depend on the menin/MLL histone methylase complex. A detailed understanding of the H3K4me3 pathway has clear clinical implications.

Technologies

Genomics: genome-wide localization of transcription factors, mRNA expression profiles, high throughput yeast two-hybrid.

Proteomics: mass spectrometry for protein identification and post-translational modifications, SILAC labeling, protein networks.

Biochemical approaches: recombinant protein expression, affinity chromatography, chromatin immunprecipitation.

Cell biology: protein tagging, live-cell imaging, confocal laser scanning.

Structural Biology

Positions available for:

Currently, there are no positions open. Nevertheless, we welcome letters of interest and CV's from prospective Ph.D. students or post-doctoral fellows. Useful past experience is protein biochemistry, molecular biology, (stem) cell biology and mass-spectrometry.

Please direct your letter to prof.dr. Marc Timmers: h.t.m.timmers -at- umcutrecht.nl