Timmers Group

Regulation of Chromatin & Transcription

Group leader: Prof. Marc Timmers (h.t.m.timmers -at- umcutrecht.nl)

Department Molecular Cancer Research, UMCU (Stratenum), Utrecht

 

Each cell in our bodies contains the same set of genes. Nevertheless, cells from different tissues perform different functions for the organism. Differential cellular functions are reflected in specific expression patterns of proteins and mRNAs, miRNAs and long non-coding RNAs. The process of RNA synthesis is tightly regulated via promoter and chromatin activation. Chromatin modifications form the basis for epigenetic regulation mechanisms.

Accessibility of promoter sequences is key to the assembly of RNA polymerase II (pol II) pre-initiation complexes. Many cellular processes involve the activation of gene-specific transcription factors and coactivator complexes, which in their turn regulate transcription initiation by pol II of specific groups of genes. On top of these protein-DNA and protein-protein interactions lies epigenetic regulation, which involves alterations in chromatin structure and modification. The combinatorial effect of histone modifications is the basis for the 'histone code'. The enzymes that introduce or remove such modifications ('writers' or 'erasers') to create binding sites for 'readers', which mediate their effects. Deregulation of transcription and chromatin pathways forms in many cases the basis for diseases like cancer and developmental disorders. In addition, distinct epigenetic pathways have been identified in stem cells.

Our research focus and technologies:

We investigate the interplay between basal transcription factors and chromatin modification in mammalian cells. In particular, how the basal transcription factor TFIID 'reads' epigenetic modifications, regulation of TFIID assembly and activity and the influence of core promoter sequences on TFIID function and dynamics of the transcription process. We are also interested in the crosstalk between different epigenetic modifications like methylation, acetylation and phosphorylation. This involves the menin protein, which is encoded by the MEN1 tumor suppressor gene mutated in Multiple Endocrine Neoplasia type 1. Menin is an integral subunit of the MLL1 'writer' complex for histone H3K4 methylation and we have shown that menin can act as an adaptor for activators like nuclear hormone receptors. This work led to our identification of menin as a breast cancer susceptibility gene.

In our research we employ state-of-the-art molecular biology, chemical biology, quantitative proteomics and cell biology techniques. This includes chromatin immunoprecipitation (ChIP), ChIP and mRNA sequencing, (live-cell) microscopy, siRNA/CRISPR gene silencing, epitope-tagging/affinity purifications, mass spectrometry, gene modification and bioreactor cultures. In our work we focus on human cancer cell lines and mouse embryonic stem cells. We have a number of (long-standing) collaborations with (inter)national groups in this exciting field.

Interested in our research and the possibility for a Major or Minor research project in our group from January 2016? Please contact Prof.dr. Marc Timmers (tel: 088-756 8981 / 8537, email: H.T.M.Timmers -at- umcutrecht.nl)