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Alternatively spliced exon regulates context-dependent MEF2D higher-order assembly during myogenesis
Mónika Gönczi1,2, João M C Teixeira3, Susana Barrera-Vilarmau3
1Department of Physiology, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032, Debrecen, Hungary.
Nature Communications
|March 10, 2023
Summary
The Myocyte-specific Enhancer Factor 2 (Mef2D) protein
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Muscle cell differentiation involves complex transcriptional regulation.
- Myocyte-specific Enhancer Factor 2 (Mef2D) plays a crucial role in this process.
- Alternative splicing of Mef2D generates a β-domain that influences its function.
Purpose of the Study:
- To investigate the role of the Mef2D β-domain in higher-order protein assembly.
- To explore the relationship between Mef2D assembly states and transcriptional activity.
- To understand how the β-domain's properties affect Mef2D's cellular localization and function during myogenesis.
Main Methods:
- Sequence analysis using the FuzDrop method.
- Live-cell imaging of Mef2D condensates and aggregates in C2C12 cells.
- Analysis of MyoD and desmin expression.
- Biophysical characterization of β-domain variants.
- Nuclear Magnetic Resonance (NMR) spectroscopy.
- Molecular dynamics (MD) simulations.
Main Results:
- The Mef2D β-domain acts as an interaction element for Mef2D higher-order assembly.
- Mef2D forms mobile nuclear condensates and solid-like cytosolic aggregates.
- Cytosolic Mef2D aggregates correlate with increased transcriptional activity and enhanced myotube development.
- β-domain variants influence the formation of liquid-like and solid-like Mef2D assemblies.
- NMR and MD simulations confirm the β-domain's ability to adopt ordered and disordered conformations.
Conclusions:
- The Mef2D β-domain dynamically regulates Mef2D higher-order assembly.
- Mef2D assembly states are fine-tuned to the cellular context, impacting transcriptional regulation.
- This regulation provides a platform for myogenic factors and the transcriptional machinery during muscle development.
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