Dimeric structure of the MADS (red) and MEF2 (green) domains of the humanMEF2B transcription factor complexed with DNA (orange) based on thePDB:1N6Jcrystallographic coordinates.The domain organization and sequence comparison of Mef2 proteins from representative species.[1] The amino acid numbering shown is of the humanMEF2A sequence and the per cent sequence identities are all relative to hMEF2A. The three domain, MADS (red), MEF2 (green), and transactivation domains (TAD; cyan) are each highlighted in a different color.
Mef2 was originally identified as a transcription factor complex throughpromoter analysis of the musclecreatine kinase (mck)gene to identify nuclear factors interacting with the mckenhancer region during muscle differentiation.[2] Three human mRNAcoding sequences designated RSRF (Related toSerum Response Factor) were cloned and shown to dimerize, bind a consensus sequence similar to the one present in the MCK enhancer region, and drive transcription.[3] RSRFs were subsequently demonstrated to encode human genes now named Mef2A, Mef2B and Mef2D.
The Mef2 gene is widely expressed in all branches ofeukaryotes fromyeast to humans. While Drosophila has a single Mef2 gene,vertebrates have at least four versions of the Mef2 gene (human versions are denoted asMEF2A,MEF2B,MEF2C, andMEF2D), allexpressed in distinct but overlapping patterns during embryogenesis through adulthood.[4]
All of the mammalian Mef2 genes share approximately 50% overall amino acid identity and about 95% similarity throughout the highly conservedN-terminal MADS-box and Mef2 domains, however their sequences diverge in theirC-terminal transactivation domain (see figure to the right).[5]
The MADS-box serves as the minimal DNA-binding domain, however an adjacent 29-amino acid extension called the Mef2 domain is required for high affinity DNA-binding and dimerization. Through an interaction with the MADS-box, Mef2 transcription factors have the ability to homo- and heterodimerize,[6] and a classic nuclear localization sequence (NLS) in the C-terminus of Mef2A, -C, and – D ensures nuclear localization of the protein.[7] D-Mef2 and human MEF2B lack this conserved NLS but are still found in the nucleus.[8]
InDrosophila, Mef2 regulates muscle development.[9] Mammalian Mef2 can cooperate withbHLH transcription factors to turn non-muscle cells in culture into muscle.[10] bHLH factors can activate Mef2c expression, which then acts to maintain its own expression.[11]
Loss of Mef2c inneural crest cells results incraniofacial defects in the developing embryo and neonatal death caused by blocking of the upper airway passages.[12][13] Mef2c upregulates the expression of thehomeodomain transcription factorsDLX5 andDLX6, two transcription factors that are necessary for craniofacial development.[12][13]
Mef2 is a critical regulator in heart development and cardiac gene expression.[16] In vertebrates, there are four genes in the Mef2 transcription factor family: Mef2a, Mef2b, Mef2c, and Mef2d. Each is expressed at specific times during development. Mef2c, the first gene to be expressed in the heart, is necessary for the development of the anterior (secondary) heart field (AHF), which helps to form components of the cardiac outflow tract and most of the right ventricle.[17][18] In addition, Mef2 genes are indicated in activating gene expression to aid in sprouting angiogenesis, the formation of new blood vessels from existing vessels.[19]
In mice, knockout studies of Mef2c have demonstrated that crucial role that it plays in heart development. Mice without the Mef2c die during embryonic day 9.5–10 with major heart defects, including improper looping, outflow tract abnormalities, and complete lack of the right ventricle.[16] This indicates improper differentiation of the anterior heart field. When Mef2c is knocked out specifically in the AHF, the mice die at birth with a range of outflow tract defects and severe cyanosis. Thus, Mef2 is necessary for many aspects of heart development, specifically by regulating the anterior heart field.[20]
MEF2, Myocyte Enhancer Factor 2, is a transcription factor with four specific numbers such as MEF2A, B, C, and D. Each MEF2 gene is located on a specific chromosome. MEF2 is known to be involved in the development and the looping of the heart (Chen) MEF2 is necessary for myocyte differentiation and gene activation (Black). Both roles contribute to the heart structure, and if there is a disruption with MEF2 in embryonic development, it can lead to two phenotypic problems (Karamboulas). The Type-I phenotype can cause severe malformations to the heart and the type-II phenotype, while it looks normal, has a thin-walled myocardium which can cause cardiac insufficiency.Another problem that can arise is from the knockout gene MEF2C. MEF2C is known to be directly related to congenital heart disease when associated with Tdgf1 (teratocarcinoma-derived growth factor 1). If MEF2C improperly regulates Tdgf1, developmental defects arise, especially within the embryonic development of the heart. (Chen). The way that MEF2C interacts with the protein Tdgf1 is through the 〖Ca〗^(2+) signaling pathway, which is required to regulate different mechanisms. MicroRNA's, non-small coding RNAs, also play a specific role in regulating MEF2C. The expression of congenital heart disease is upregulated due to the downregulation of the microRNA miR-29C (Chen). A few other known diseases associated with the MEF2 family are liver fibrosis, cancers, and neurodegenerative diseases (Chen).
^McKinsey TA, Zhang CL, Olson EN (2002). "MEF2: a calcium-dependent regulator of cell division, differentiation and death".Trends Biochem. Sci.27 (1):40–7.doi:10.1016/S0968-0004(01)02031-X.PMID11796223.
^Black BL, Olson EN (1998). "Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins".Annu Rev Cell Dev Biol.14:167–96.doi:10.1146/annurev.cellbio.14.1.167.PMID9891782.
^Borghi S, Molinari S, Razzini G, Parise F, Battini R, Ferrari S (2001). "The nuclear localization domain of the Mef2 family of transcription factors shows member-specific features and mediates the nuclear import of histone deacetylase 4".J Cell Sci.114 (Pt 24):4477–83.doi:10.1242/jcs.114.24.4477.PMID11792813.
^Barnes RM, Harris IS, Jaehnig EJ, Sauls K, Sinha T, Rojas A, Schachterle W, McCulley DJ, Norris RA, Black BL. (January 2016). "Mef2c regulates outflow tract alignment and transcriptional control of Tdgf1." Development. 143: 774-779. oi:10.1242/dev.126383
Black, Brian L., and Richard M. Cripps. “Myocyte Enhancer Factor 2 Transcription Factors in Heart Development and Disease.” Heart Development and Regeneration, 2010, pp. 673–699., doi:10.1016/b978-0-12-381332-9.00030-x.
Chen, Xiao, et al. “MEF2 Signaling and Human Diseases.” Oncotarget, vol. 8, no. 67, 2017, pp. 112152–112165., doi:10.18632/oncotarget.22899.
Karamboulas, C., et al. “Disruption of MEF2 Activity in Cardiomyoblasts Inhibits Cardiomyogenesis.” Journal of Cell Science, vol. 120, no. 1, 2006, pp. 4315–4318., doi:10.1242/jcs.03369.
