Endogenous bioluminescent reporters reveal a sustained increase in utrophin gene expression upon EZH2 and ERK1/2 inhibition.

Autor: Gleneadie HJ; Epigenetic Memory Group, MRC London Institute of Medical Sciences (LMS), Imperial College London, Du Cane Road, London, W12 0NN, UK., Fernandez-Ruiz B; Epigenetic Memory Group, MRC London Institute of Medical Sciences (LMS), Imperial College London, Du Cane Road, London, W12 0NN, UK., Sardini A; Whole Animal Physiology and Imaging Facility, MRC LMS, Imperial College London, Du Cane Road, London, W12 0NN, UK., Van de Pette M; Epigenetic Memory Group, MRC London Institute of Medical Sciences (LMS), Imperial College London, Du Cane Road, London, W12 0NN, UK.; MRC Toxicology Unit, Gleeson Building, Tennis Court Road, Cambridge, CB2 1QR, UK., Dimond A; Epigenetic Memory Group, MRC London Institute of Medical Sciences (LMS), Imperial College London, Du Cane Road, London, W12 0NN, UK., Prinjha RK; Immunology and Epigenetics Research Unit, Research, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK., McGinty J; Photonics Group, Department of Physics, Blackett Laboratory, Imperial College London, London, SW7 2AZ, UK., French PMW; Photonics Group, Department of Physics, Blackett Laboratory, Imperial College London, London, SW7 2AZ, UK., Bagci H; Lymphocyte Development Group, MRC LMS, Imperial College London, Du Cane Road, London, W12 0NN, UK., Merkenschlager M; Lymphocyte Development Group, MRC LMS, Imperial College London, Du Cane Road, London, W12 0NN, UK., Fisher AG; Epigenetic Memory Group, MRC London Institute of Medical Sciences (LMS), Imperial College London, Du Cane Road, London, W12 0NN, UK. amanda.fisher@lms.mrc.ac.uk.; Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU, Oxford, UK. amanda.fisher@lms.mrc.ac.uk.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2023 Mar 25; Vol. 6 (1), pp. 318. Date of Electronic Publication: 2023 Mar 25.
DOI: 10.1038/s42003-023-04666-9
Abstrakt: Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by loss of function mutations in the dystrophin gene (Dmd), resulting in progressive muscle weakening. Here we modelled the longitudinal expression of endogenous Dmd, and its paralogue Utrn, in mice and in myoblasts by generating bespoke bioluminescent gene reporters. As utrophin can partially compensate for Dmd-deficiency, these reporters were used as tools to ask whether chromatin-modifying drugs can enhance Utrn expression in developing muscle. Myoblasts treated with different PRC2 inhibitors showed significant increases in Utrn transcripts and bioluminescent signals, and these responses were independently verified by conditional Ezh2 deletion. Inhibition of ERK1/2 signalling provoked an additional increase in Utrn expression that was also seen in Dmd-mutant cells, and maintained as myoblasts differentiate. These data reveal PRC2 and ERK1/2 to be negative regulators of Utrn expression and provide specialised molecular imaging tools to monitor utrophin expression as a therapeutic strategy for DMD.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje