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

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.

Exploring Multi-Tissue Alternative Splicing and Skeletal Muscle Metabolism Regulation in Obese- and Lean-Type Pigs

“…Simultaneously, a transcript of the PYGM (ENSSSCT00000059278) was not detected in Duroc pigs. Due to the increasing focus on the diverse regulatory functions exhibited by different protein isoforms encoded by the same gene [66][67][68][69], we contemplate whether the specific transcripts of these three genes contribute to the phenotypic differences observed in skeletal muscles between the two pig breeds.…”

Migration of Myogenic Cells Is Highly Influenced by Cytoskeletal Septin7

“…Several regulatory proteins (transcription and myogenic regulatory factors) that control the fusion of myoblasts into myotubes are probably involved in this alteration. In a recent study, the importance of alternative splicing and the dynamic variability of the Mef2D transcription factor in the process of myogenic differentiation were described [54]. In addition, several signaling pathways that are involved in skeletal myogenesis, such as the p38α/β mitogen-activated protein kinase (MAPK) pathway in which the Rho family of small GTPases including Rac1, Cdc42, and RhoA [55] could also play a role.…”