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H2020Individual fellowship2015–2017

KMET-READ · Reading of lysine methylation – discovery, biological function and application

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2015-10-01 → 2017-09-30
EU contribution
€171,461
Participants
1
Scheme
MSCA-IF-EF-ST

Lines connect the coordinator with its partners.

Results in brief

Reading of lysine methylation – discovery, biological function and application

Posttranslational modifications (PTMs) of proteins are utilized by eukaryotic cells to structurally and functionally diversify the proteome. Protein methylation gained especially interest as methylation of lysine residues of histones modulates chromatin structure, gene expression and mammalian development. Lysine methylation marks manifest their biological effect via so-called ‘readers’ (or reading domains) which bind specific methylated lysine residues and induce biological responses. Reading domains include Plant homeodomains (PHD) and Chromodomains (CD) found in many chromatin proteins. Still, even though many proteins have reading domains in their structure, the function of them is not entirely understood. Even more, over last two decades, more than fifty lysine-specific methyltransferases were identified which methylate a large number of histone and non-histone proteins and considering the diversity of the methylome, the list of already known readers is unlikely to be exhaustive. The primary goal of the KMET-READ project was to investigate the biological role of reading domains in essential histone lysine methyltransferases - PHDs in MLL2 (KMT2C) and MLL3 (KMT2D) and CDs in SUV39H1. Importantly, the KMET-READ project aimed also to develop a yeast-3-hybrid method for the identification of new reading domains, which will allow discovering binding partners for just recently characterized new protein methylation marks. The objectives of this project participate in enlightening the molecular network involved in PTM recognition which also has high relevance in diseases like cancer or developmental abnormalities. Importantly the project brought development of a new tool that should allow in the cost-effective and relatively easy way identify new methylation readers.

Data: CORDIS, © European Union

Project objective

Protein methylation at lysine residues modulates chromatin structure, affects gene expression and mammalian development. Recently, it was also shown to influence the stability and activity of non-histone proteins. Lysine methylation marks manifest their biological effect via so-called ‘readers’ (or reading domains) which recognize and bind the methylation mark and directly alter the chromatin structure or act as a scaffold for other proteins, which induce biological responses. Reading domains include Plant homeodomains (PHD) and Chromodomains (CD) found in many chromatin proteins. KMET-READ plans to investigate the biological role of these reading domains in essential histone lysine methyltransferases - PHDs in MLL2 and MLL3 and CDs in SUV39H1 and SUV39H2. The results obtained here will advance the understanding of chromatin changes in human cells. The proposal will apply an interdisciplinary approach in an international environment to maximize its chances of success: the biological role of reading domains will be evaluated with molecular biology (histone and chromatin pulldowns, ChIP-seq, confocal microscopy), biochemistry (Peptide arrays, mass spectrometry, methyltransferase activity assays) and biophysics techniques (fluorescence anisotropy, circular dichroism spectroscopy) as well as crystallography (solving the structure of reading domains). Importantly, the KMET-READ project will also develop a yeast-3-hybrid method for the identification of new reading domains, which will allow to discover binding partners for just recently characterized new protein methylation marks. This novel method will be patented and introduced into market. All project partners will ensure an efficient dissemination and communication of the results of the KMET-READ project. The project will provide excellent training in research methods and other skills for the fellow that will strongly support her future career and initiate new and sustainable collaborations between the partners.

Original text from CORDIS.

Participants

  • UNIVERSITY OF STUTTGART · StuttgartCoordinatorGermany

Links

Data: CORDIS, © European Union