FoxP1 Represses MEF2A in Striated Muscle

Area of Science:

• Molecular and Cellular Biology
• Developmental Biology
• Cardiovascular Research

Background:

• Myocyte enhancer factor 2 (MEF2) proteins regulate diverse vertebrate developmental, physiological, and pathological processes.
• Understanding MEF2A's protein interactions is vital due to its involvement in numerous biological functions.

Purpose of the Study:

• To comprehensively characterize the MEF2A interactome.
• To investigate the functional consequences of MEF2A's interaction with the transcriptional repressor FOXP1.

Main Methods:

• Utilized a nanobody-based affinity-purification coupled with mass spectrometry (AP-MS) strategy.
• Employed GFP-tagged MEF2A and a GBP-nanobody for capturing MEF2A protein complexes from myogenic lysates.
• Performed Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) for proteomic analysis and identified interactors.

Main Results:

• Identified FOXP1 as a MEF2A interactor that coprecipitates with MEF2A in proliferating myogenic cells, with reduced interaction upon differentiation.
• Demonstrated that ectopic FOXP1 expression inhibits MEF2A-driven myogenic reporter genes and delays endogenous myogenin induction.
• Showed that FOXP1 depletion enhances MEF2A transactivation and myogenin expression; this interaction is preserved in cardiomyocytes, where FOXP1 depletion promotes hypertrophy.

Conclusions:

• FOXP1 acts as a negative regulator of MEF2A activity, preventing premature myogenic progenitor differentiation.
• FOXP1 restricts MEF2A function, potentially preventing the re-activation of embryonic gene expression in conditions like cardiomyocyte hypertrophy.
• The MEF2A-FOXP1 interaction plays a significant role in muscle development and cardiac pathophysiology.