Myocyte enhancer factor 2 (MEF2) proteins play a key role in promoting the expression of muscle-specific genes in differentiated muscle cells. MEF2 activity is regulated by the association with several transcriptional co-factors and by post-translational modifications. In the present report, we provide evidence for a novel regulatory mechanism of MEF2C activity, which occurs at the onset of skeletal muscle differentiation and is based on Lys4 acetylation. This covalent modification results in the enhancement of MEF2C binding to DNA and chromatin. In particular, we report that the kinetic parameters of MEF2/ DNA association change substantially upon induction of differentiation to give a more stable complex and that this effect is mediated by Lys4 acetylation. We also show that Lys4 acetylation plays a prominent role in the p300-dependent activation of MEF2C.
Bibliographical noteFunding Information:
We are grateful to Roberto Mantovani for baculovirus expressed p300, Phil Cole for the p300 inhibitor LysCoA, Margaret Buckingham for the C2C7 muscle cell line, Stefano Schiaffino for the pGL3(desMEF2)3 reporter vector. We are indebted to Rossella Tupler, Margaret Buckingham and Graziella Messina for critically reading the manuscript and to Francesca Fanelli and Laurence Vandel for helpful discussions. We are also indebted to Andrea Tombesi (Centro Grandi Strumenti, University of Modena and Reggio Emilia) for technical assistance with the confocal microscope and to Alessandra Agresti for precious advices regarding the FRAP experiments. We thank Renata Battini for assistance and for numerous discussions and Alessio Polacchini for the purification and acetylation of the recombinant bacterial protein. This work was funded by Telethon (GP0210Y01); MURST-COFIN’04 and MURST COFIN’06 to S.F. Funding to pay the Open Access publication charges for this article was provided by MURST COFIN’06.