FoxP1 represses MEF2A in striated muscle

Myocyte Enhancer Factor 2 (MEF2) is a transcription factor complex encoded by genes mef2a-d. MEF2 proteins belong to the MADS-box DNA binding protein superfamily involved in many developmental pathways including myogenesis and the survival of cardiomyocytes. MEF2 proteins interact with myogenic regulatory factors and modulate the expression of muscle-specific genes. Thus, unbiased characterization of the MEF2A interactome would expand our understanding of MEF2 functions. A GFP-nanotrap purification followed by LC-MS/MS proteomic analysis was employed to identify MEF2A interacting proteins. Following gene ontology analysis, we focused on an interaction between MEF2A and its novel interacting protein, FOXP1, in striated muscle. FOXP1 was found in the MEF2A-immunocomplex in muscle cells, and ectopic expression of FOXP1 delays myogenic differentiation. FOXP1 inhibited MEF2A activation on myogenic reporter genes driven by the regulatory regions of creatine kinase muscle and myogenin genes. Additionally, siRNA-mediated deletion of FOXP1 in myoblasts and cardiomyocytes enhances MEF2A transactivation properties. Lastly, various biochemical experiments indicate that FOXP1 antagonizes p38 MAPK activation of MEF2A through Threonine-312 phosphorylation. Collectively, we documented a novel repressive interaction of FOXP1 and MEF2A in proliferating striated muscle cells.