Menin/MLL complexes in chromatin regulation

Abstract

Transcription regulation of genes is controlled by the chemical modification of histone proteins that pack the DNA into a higher order structure. These epigenetic modifications can influence protein-protein and protein-DNA contacts but can also directly recruit effector proteins to certain genomic sites. Lysine 4 tri-methylation on histone H3 (H3K4me3) is deposited by the SET1/MLL multisubunit complexes. H3K4me3 is found almost exclusively at promoters of active genes where it can recruit effector proteins such as the basal transcription factor TFIID. As part of my PhD training in the lab of Prof. Marc Timmers at the University Medical Center Utrecht, we have studied the molecular interactions that are involved in the regulation of transcription through this histone modification. Several of the factors involved have been implicated in diseases such as cancer. We have particularly explored the role of the MLL component Menin. This tumor suppressor protein in mutated in the familial Multiple Endocrine Neoplasia Type 1 syndrome (MEN1) and we have studied its function and the Menin associating proteins in much detail. A combination of cell biology, biochemistry, proteomics, NMR and genomics approaches on the components that deposit and recognize H3K4me have led to four major findings: 1) The basal transcription factor TFIID binds simultaneous to promoter associated histone modifications and DNA sequences. 2) SET1/MLL complexes are highly heterogeneous and contain multiple sub-stoichiometric components. 3) The MLL subunit PSIP1 contains a PWWP-domain and we have found that PWWP domains are specific H3K36me readers that rely on DNA binding for stable association with nucleosomes. 4) Menin is important for vitamin D receptor function in MEN1 related tumors.