Alternatively spliced exon regulates context-dependent MEF2D higher-order assembly during myogenesis

Mónika Gönczi, João M. C. Teixeira, Susana Barrera-Vilarmau, Laura Mediani, Francesco Antoniani, Tamás Milán Nagy, Krisztina Fehér, Zsolt Ráduly, Viktor Ambrus, József Tőzsér, Endre Barta, Katalin E. Kövér, László Csernoch, Serena Carra () and Monika Fuxreiter ()
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Mónika Gönczi: University of Debrecen
João M. C. Teixeira: University of Padova
Susana Barrera-Vilarmau: University of Padova
Laura Mediani: University of Modena and Reggio Emilia G. Campi 287
Francesco Antoniani: University of Modena and Reggio Emilia G. Campi 287
Tamás Milán Nagy: University of Debrecen
Krisztina Fehér: University of Debrecen
Zsolt Ráduly: University of Debrecen
Viktor Ambrus: University of Debrecen
József Tőzsér: University of Debrecen
Endre Barta: University of Debrecen
Katalin E. Kövér: University of Debrecen
László Csernoch: University of Debrecen
Serena Carra: University of Modena and Reggio Emilia G. Campi 287
Monika Fuxreiter: University of Padova

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract During muscle cell differentiation, the alternatively spliced, acidic β-domain potentiates transcription of Myocyte-specific Enhancer Factor 2 (Mef2D). Sequence analysis by the FuzDrop method indicates that the β-domain can serve as an interaction element for Mef2D higher-order assembly. In accord, we observed Mef2D mobile nuclear condensates in C2C12 cells, similar to those formed through liquid-liquid phase separation. In addition, we found Mef2D solid-like aggregates in the cytosol, the presence of which correlated with higher transcriptional activity. In parallel, we observed a progress in the early phase of myotube development, and higher MyoD and desmin expression. In accord with our predictions, the formation of aggregates was promoted by rigid β-domain variants, as well as by a disordered β-domain variant, capable of switching between liquid-like and solid-like higher-order states. Along these lines, NMR and molecular dynamics simulations corroborated that the β-domain can sample both ordered and disordered interactions leading to compact and extended conformations. These results suggest that β-domain fine-tunes Mef2D higher-order assembly to the cellular context, which provides a platform for myogenic regulatory factors and the transcriptional apparatus during the developmental process.

Date: 2023
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DOI: 10.1038/s41467-023-37017-7

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