Chemical biology approaches to unraveling the histone code

Informazioni relative al progetto

EPITOOLS

ID dell’accordo di sovvenzione: 679479

DOI

10.3030/679479

Progetto chiuso

Data della firma CE 15 Febbraio 2016

Data di avvio 1 Aprile 2016

Data di completamento 30 Settembre 2021

Finanziato da

• EXCELLENT SCIENCE - European Research Council (ERC)

Costo totale

€ 1 758 846,00

Contributo UE

€ 1 758 846,00

Coordinato da

UNIVERSITY OF NEWCASTLE UPON TYNE
United Kingdom

Periodic Reporting for period 4 - EPITOOLS (Chemical biology approaches to unraveling the histone code)

Periodo di rendicontazione: 2019-10-01 al 2021-09-30

Sintesi del contesto e degli obiettivi generali del progetto

Posttranslational modifications on histones play crucial roles in the epigenetic regulation of eukaryotic gene expression. Chemical modifications that occur on histone tails include acetylation, methylation, phosphorylation, ubiquitination. This chemical diversity together with the positions and combinations of these modifications give rise to complex networks of highly controlled gene expression programs. The identification and characterisation of chromatin-associated proteins (or epigenetic regulators) in recent years has advanced our understanding of the significance of these histone modifications and the regulatory outcomes in development and in disease. The project aims to generate new classes of highly selective and potent chemical probes for epigenetic regulators, focusing on enzymes and proteins associated with methyl-lysine marks. A novel modified peptide-based discovery platform, which combines molecular, chemical, biophysical and cellular techniques, have been developed and applied. These chemical probes will be useful for biological and biomedical research, and will serve as potential starting points for therapeutic epigenetic intervention.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

We have successfully generated macrocyclic peptide probes for histone demethylase KDM4 subfamily. Cell activity of the peptides was optimised via systematic structure- and mass spectrometry guided design. The probes have been widely distributed for cellular testing in the context of multiple diseases. Work towards understanding peptide features for cell-permeability has been made. Further we have made important progress in targeting other 'challenging' epigenetic protein targets, such as the methyl lysine reader domains, and have identified potent peptide ligands which have been used as tools for mechanistic and kinetic studies. High affinity cyclic peptide-based tools have also been developed as reagents complementary to antibodies for studying target proteins and protein-protein complexes in cellular context.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

Our work to date have exemplified the use of diverse peptide-based approaches for studying epigenetic regulation. We have generated cyclic peptide probes that inhibit the histone demethylases via catalytic domains or allosteric sites, with unprecedented high affinity and selectivity. These probes are currently being tested in biological assays in multiple disease context. These tools will be useful in target validation, as well as to enable future design of epigenetic-targeted therapeutics.

Crystal structure of a histone demethylase KDM4A in complex with a cyclic peptide