Myocyte Enhancer Factor 2A Is Transcriptionally Autoregulated

Diabetes Research Laboratory, Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2008; 283(16):10318-29. DOI: 10.1074/jbc.M707623200
Source: PubMed


MEF2 (myocyte enhancer factor 2) proteins are a small family of transcription factors that play pivotal roles in striated muscle differentiation, development, and metabolism, in neuron survival and synaptic formation, and in lymphocyte selection and activation. Products of the four mammalian MEF2 genes, MEF2A, MEF2B, MEF2C, and MEF2D, are expressed with overlapping but distinct temporospatial patterns. Toward analysis of MEF2A functions and the determinants of its regulated expression, we have mapped and begun studies of the transcriptional control regions of this gene. Heterogeneous 5'-untranslated regions of MEF2A mRNAs result from use of alternative promoters and splicing patterns. The two closely approximated TATA-less promoters are approximately 65 kb upstream of the exon containing the sole initiation codon. Ribonuclease protection and primer extension assays show that each promoter is active in various adult tissues. A canonical MEF2 site overlies the major promoter 1 transcription start site. This element specifically binds MEF2 factors, including endogenous nuclear MEF2A according to chromatin immunoprecipitation studies, and is critical to MEF2A transcription in myocytes. The site exerts reciprocal control of the alternative promoters, silencing promoter 1 and activating promoter 2 under some conditions. Erk5 and p38 MAPK signaling stimulate MEF2A expression by activating both promoters from the MEF2 element. MEF2A transcription is therefore subject to positive or negative regulation by its protein products, depending on signaling activities that influence MEF2 factor trans-activity. The sole MEF2 gene of the cephalochordate amphioxus has a similar regulatory region structure, suggesting that this mode of autoregulatory control is conserved among higher metazoan MEF2 genes.

9 Reads
  • Source
    • "2 binding sites of the human Sirt1 pro - moter are neither conserved in mouse nor in other non - human species . This is surprising in view that Sirt1 plays a major role in several physiological processes ( Sugden et al . , 2010 ) . However , it is still possible that MEF2 regulates Sirt1 expression without directly binding to Sirt1 promoter DNA ( Ramachandran et al . , 2008b ) and that humans have developed a new , more direct pathway , for Sirt1 regulation by direct MEF2 binding to the promoter that could provide an evolutionary advantage ."
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer cell metabolism differs from that of non-transformed cells in the same tissue. This specific metabolism gives tumor cells growing advantages besides the effect in increasing anabolism. One of these advantages is immune evasion mediated by a lower expression of the mayor histocompatibility complex class I molecules. The extracellular-signal-regulated kinase-5 regulates both mayor histocompatibility complex class I expression and metabolic activity. However, the mechanisms underlying are largely unknown. We show here that extracellular-signal-regulated kinase-5 regulates the transcription of the NADH(+)-dependent histone deacetylase silent mating type information regulation 2 homolog 1 (Sirtuin 1) in leukemic Jurkat T cells. This involves the activation of the transcription factor myocyte enhancer factor-2 and its binding to the sirt1 promoter. In addition, extracellular-signal-regulated kinase-5 is required for T cell receptor-induced and oxidative stress-induced full Sirtuin 1 expression. Extracellular-signal-regulated kinase-5 induces the expression of promoters containing the antioxidant response elements through a Sirtuin 1-dependent pathway. On the other hand, down modulation of extracellular-signal-regulated kinase-5 expression impairs the anti-oxidant response. Notably, the extracellular-signal-regulated kinase-5 inhibitor BIX02189 induces apoptosis in acute myeloid leukemia tumor cells without affecting T cells from healthy donors. Our results unveil a new pathway that modulates metabolism in tumor cells. This pathway represents a promising therapeutic target in cancers with deep metabolic layouts such as acute myeloid leukemia.
    The International Journal of Biochemistry & Cell Biology 05/2014; 53. DOI:10.1016/j.biocel.2014.05.026 · 4.05 Impact Factor
  • Source
    • "Known TF-to-TF Circuitry To assess the accuracy of cellular TF regulatory networks derived from DNaseI footprints, we analyzed several well-annotated mammalian cell-type-specific transcriptional regulatory subnetworks (Figures 1B and 1C). The muscle-specific factors MyoD, Myogenin (MYOG), MEF2A, and MYF6 form a network that was uncovered using a combination of genetic and physical studies, including DNaseI footprinting, and is vital for specification of skeletal muscle fate and control of myogenic development and differentiation (Naidu et al., 1995; Yun and Wold, 1996; Ramachandran et al., 2008). Figure 1B juxtaposes the known regulatory interactions between these factors determined Cell 150, 1274–1286, September 14, 2012 ª2012 Elsevier Inc. 1275 A "
    [Show abstract] [Hide abstract]
    ABSTRACT: The combinatorial cross-regulation of hundreds of sequence-specific transcription factors (TFs) defines a regulatory network that underlies cellular identity and function. Here we use genome-wide maps of in vivo DNaseI footprints to assemble an extensive core human regulatory network comprising connections among 475 sequence-specific TFs and to analyze the dynamics of these connections across 41 diverse cell and tissue types. We find that human TF networks are highly cell selective and are driven by cohorts of factors that include regulators with previously unrecognized roles in control of cellular identity. Moreover, we identify many widely expressed factors that impact transcriptional regulatory networks in a cell-selective manner. Strikingly, in spite of their inherent diversity, all cell-type regulatory networks independently converge on a common architecture that closely resembles the topology of living neuronal networks. Together, our results provide an extensive description of the circuitry, dynamics, and organizing principles of the human TF regulatory network.
    Cell 09/2012; 150(6):1274-86. DOI:10.1016/j.cell.2012.04.040 · 32.24 Impact Factor
  • Source
    • "MEF2 binds directly to the promoters or enhancers of the majority of muscle-specific genes (Naya and Olson, 1999), and virtually all muscle genes, including MRFs, have MEF2 binding sites in their regulatory regions (Messina et al., 2010). The MADS box and adjacent MEF2 domain of MEF2 proteins play a cooperative role in binding to the regulatory regions of muscle genes (Potthoff and Olson, 2007; Ramachandran et al., 2008) to activate skeletal muscle differentiation. However, unlike MRFs, MEF2 factors cannot activate myogenesis alone but, instead, combine with MRFs through protein-protein interactions in the MADS box and bHLH domain to vastly improve the efficiency of the myogenic program (Kaushal et al., 1994). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of myogenic enhancer transcription factor 2a (MEF2A) in avian muscle during fetal development is unknown. In this work, we cloned the duck MEF2A cDNA sequence (GenBank accession no. HM460752) and examined its developmental expression profiles in cardiac muscle, non-vascular smooth muscle and skeletal muscle. Duck MEF2A cDNA comprised 1479 bp encoding 492 amino acid residues. In silico analysis showed that MEF2A contained MADS (MCM1, AGAMOUS, DEFICIENS and SRF - serum response factor), MEF2 and mitogen-activated protein kinase (MAPK) transcription domains with high homology to related proteins in other species. Modified sites in these domains were conserved among species and several variants were found. Quantitative PCR showed that MEF2A was expressed in all three muscles at each developmental stage examined, with the expression in smooth muscle being higher than in the other muscles. These results indicate that the conserved domains of duck MEF2A, including the MADS and MEF2 domains, are important for MEF2A transcription factor function. The expression of MEF2A in duck smooth muscle and cardiac muscle suggests that MEF2A plays a role in these two tissues.
    Genetics and Molecular Biology 02/2012; 35(1):182-90. DOI:10.1590/S1415-47572012005000023 · 1.20 Impact Factor
Show more


9 Reads
Available from