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1
Zhao, Ming, Liguo New, Vladimir V. Kravchenko, Yutaka Kato, Hermann Gram, Franco di Padova, Eric N. Olson, Richard J. Ulevitch, and Jiahuai Han. "Regulation of the MEF2 Family of Transcription Factors by p38." Molecular and Cellular Biology 19, no. 1 (January 1, 1999): 21–30. http://dx.doi.org/10.1128/mcb.19.1.21.
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ABSTRACT Members of the MEF2 family of transcription factors bind as homo- and heterodimers to the MEF2 site found in the promoter regions of numerous muscle-specific, growth- or stress-induced genes. We showed previously that the transactivation activity of MEF2C is stimulated by p38 mitogen-activated protein (MAP) kinase. In this study, we examined the potential role of the p38 MAP kinase pathway in regulating the other MEF2 family members. We found that MEF2A, but not MEF2B or MEF2D, is a substrate for p38. Among the four p38 group members, p38 is the most potent kinase for MEF2A. Threonines 312 and 319 within the transcription activation domain of MEF2A are the regulatory sites phosphorylated by p38. Phosphorylation of MEF2A in a MEF2A-MEF2D heterodimer enhances MEF2-dependent gene expression. These results demonstrate that the MAP kinase signaling pathway can discriminate between different MEF2 isoforms and can regulate MEF2-dependent genes through posttranslational activation of preexisting MEF2 protein.
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Li, Lucy, Lewis P. Rubin, and Xiaoming Gong. "MEF2 transcription factors in human placenta and involvement in cytotrophoblast invasion and differentiation." Physiological Genomics 50, no. 1 (January 1, 2018): 10–19. http://dx.doi.org/10.1152/physiolgenomics.00076.2017.
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Development of the human placenta and its trophoblast cell types is critical for a successful pregnancy. Defects in trophoblast invasion and differentiation are associated with adverse pregnancy outcomes, including preeclampsia. The members of myocyte enhancer factor-2 (MEF2) family of transcription factors are key regulators of cellular proliferation, differentiation, and invasion in various cell types and tissues and might play a similarly important role in regulating trophoblast proliferation, invasion, and differentiation during human placental development. In the present study, using human cytotrophoblast cell lines (HTR8/SVneo and BeWo) and primary human cytotrophoblasts (CTBs), we show that members of the MEF2 family are differentially expressed in human placental CTBs, with MEF2B and MEF2D being highly expressed in first trimester extravillous CTBs. Overexpression of MEF2D results in cytotrophoblast proliferation and enhances the invasion and migration of extravillous-like HTR8/SVneo cells. This invasive property is blocked by overexpression of a dominant negative MEF2 (dnMEF2). In contrast, MEF2A is the principal MEF2 isoform expressed in term CTBs, MEF2C and MEF2D being expressed more weakly, and MEF2B expression being undetected. Overexpression of MEF2A induces cytotrophoblast differentiation and syncytium formation in BeWo cells. During in vitro differentiation of primary CTBs, MEF2A expression is associated with CTB differentiation into syncytiotrophoblast. Additionally, the course of p38 MAPK and ERK5 activities parallels the increase in MEF2A expression. These findings suggest individual members of MEF2 family distinctively regulate cytotrophoblast proliferation, invasion, and differentiation. Dysregulation of expression of MEF2 family or of their upstream signaling pathways may be associated with placenta-related pregnancy disorders.
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Di Giorgio, Eros, Enrico Gagliostro, Andrea Clocchiatti, and Claudio Brancolini. "The Control Operated by the Cell Cycle Machinery on MEF2 Stability Contributes to the Downregulation of CDKN1A and Entry into S Phase." Molecular and Cellular Biology 35, no. 9 (March 2, 2015): 1633–47. http://dx.doi.org/10.1128/mcb.01461-14.
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MEF2s are pleiotropic transcription factors (TFs) which supervise multiple cellular activities. During the cell cycle, MEF2s are activated at the G0/G1transition to orchestrate the expression of the immediate early genes in response to growth factor stimulation. Here we show that, in human and murine fibroblasts, MEF2 activities are downregulated during late G1. MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding. Unscheduled MEF2 transcription during the cell cycle reduces cell proliferation, whereas its containment sustains DNA replication. The CDK inhibitor p21/CDKN1A gene is a MEF2 target gene required to exert this antiproliferative influence. MEF2C and MEF2D bind a region within the first intron ofCDKN1A, presenting epigenetic markers of open chromatin. Importantly, H3K27 acetylation within this regulative region depends on the presence of MEF2D. We propose that following the initial engagement in the G0/G1transition, MEF2C and MEF2D must be polyubiquitylated and degraded during G1progression to diminish the transcription of theCDKN1Agene, thus favoring entry into S phase.
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Edmondson, D. G., G. E. Lyons, J. F. Martin, and E. N. Olson. "Mef2 gene expression marks the cardiac and skeletal muscle lineages during mouse embryogenesis." Development 120, no. 5 (May 1, 1994): 1251–63. http://dx.doi.org/10.1242/dev.120.5.1251.
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Members of the MEF2 family of transcription factors bind a conserved A/T-rich sequence in the control regions of many skeletal and cardiac muscle genes. To begin to assess the roles of the different Mef2 genes in the control of muscle gene expression in vivo, we analyzed by in situ hybridization the expression patterns of the Mef2a, Mef2c and Mef2d genes during mouse embryogenesis. We first detected MEF2C expression at day 7.5 postcoitum (p.c.) in cells of the cardiac mesoderm that give rise to the primitive heart tube, making MEF2C one of the earliest markers for the cardiac muscle lineage yet described. By day 8.5, MEF2A, MEF2C and MEF2D mRNAs are all detected in the myocardium. By day 9.0, MEF2C is expressed in rostral myotomes, where its expression lags by about a day behind that of myf5 and several hours behind that of myogenin. MEF2A and MEF2D are expressed at a lower level than MEF2C in the myotome at day 9.5 and are detected in more embryonic tissues than MEF2C. Expression of each of the MEF2 transcripts is observed in muscle-forming regions within the limbs at day 11.5 p.c. and within muscle fibers throughout the embryo at later developmental stages. The expression of MEF2C in the somites and fetal muscle is distinct from that of MEF2A, MEF2D and the myogenic bHLH regulatory genes, suggesting that it may represent a distinct myogenic cell type. Neural crest cells also express high levels of MEF2 mRNAs between days 8.5 and 10.5 of gestation. After day 12.5 p.c., MEF2 transcripts are detected at high levels in specific regions of the brain and ultimately in a wide range of tissues. The distinct patterns of expression of the different Mef2 genes during mouse embryogenesis suggest that these genes respond to unique developmental cues and support the notion that their products play roles in the regulation of muscle-specific transcription during establishment of the cardiac and skeletal muscle lineages.
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Martin, J. F., J. M. Miano, C. M. Hustad, N. G. Copeland, N. A. Jenkins, and E. N. Olson. "A Mef2 gene that generates a muscle-specific isoform via alternative mRNA splicing." Molecular and Cellular Biology 14, no. 3 (March 1994): 1647–56. http://dx.doi.org/10.1128/mcb.14.3.1647-1656.1994.
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Members of the myocyte-specific enhancer-binding factor 2 (MEF2) family of transcription factors bind a conserved A/T-rich sequence in the control regions of numerous muscle-specific genes. Mammalian MEF2 proteins have been shown previously to be encoded by three genes, Mef2, xMef2, and Mef2c, each of which gives rise to multiple alternatively spliced transcripts. We describe the cloning of a new member of the MEF2 family from mice, termed MEF2D, which shares extensive homology with other MEF2 proteins but is the product of a separate gene. MEF2D binds to and activates transcription through the MEF2 site and forms heterodimers with other members of the MEF2 family. Deletion mutations show that the carboxyl terminus of MEF2D is required for efficient transactivation. MEF2D transcripts are widely expressed, but alternative splicing of MEF2D transcripts gives rise to a muscle-specific isoform which is induced during myoblast differentiation. The mouse Mef2, Mef2c, and Mef2d genes map to chromosomes 7, 13, and 3, respectively. The complexity of the MEF2 family of regulatory proteins provides the potential for fine-tuning of transcriptional responses as a consequence of combinatorial interactions among multiple MEF2 isoforms encoded by the four Mef2 genes.
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Martin, J. F., J. M. Miano, C. M. Hustad, N. G. Copeland, N. A. Jenkins, and E. N. Olson. "A Mef2 gene that generates a muscle-specific isoform via alternative mRNA splicing." Molecular and Cellular Biology 14, no. 3 (March 1994): 1647–56. http://dx.doi.org/10.1128/mcb.14.3.1647.
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Members of the myocyte-specific enhancer-binding factor 2 (MEF2) family of transcription factors bind a conserved A/T-rich sequence in the control regions of numerous muscle-specific genes. Mammalian MEF2 proteins have been shown previously to be encoded by three genes, Mef2, xMef2, and Mef2c, each of which gives rise to multiple alternatively spliced transcripts. We describe the cloning of a new member of the MEF2 family from mice, termed MEF2D, which shares extensive homology with other MEF2 proteins but is the product of a separate gene. MEF2D binds to and activates transcription through the MEF2 site and forms heterodimers with other members of the MEF2 family. Deletion mutations show that the carboxyl terminus of MEF2D is required for efficient transactivation. MEF2D transcripts are widely expressed, but alternative splicing of MEF2D transcripts gives rise to a muscle-specific isoform which is induced during myoblast differentiation. The mouse Mef2, Mef2c, and Mef2d genes map to chromosomes 7, 13, and 3, respectively. The complexity of the MEF2 family of regulatory proteins provides the potential for fine-tuning of transcriptional responses as a consequence of combinatorial interactions among multiple MEF2 isoforms encoded by the four Mef2 genes.
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Aude-Garcia, Catherine, Véronique Collin-Faure, Huguette Bausinger, Daniel Hanau, Thierry Rabilloud, and Claudie Lemercier. "Dual roles for MEF2A and MEF2D during human macrophage terminal differentiation and c-Jun expression." Biochemical Journal 430, no. 2 (August 13, 2010): 237–44. http://dx.doi.org/10.1042/bj20100131.
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Recent reports have evidenced a role for MEF2C (myocyte enhancer factor 2C) in myelopoiesis, although the precise functions of this transcription factor are still unclear. We show in the present study that MEF2A and MEF2D, two other MEF2 family members, are expressed in human primary monocytes and in higher amounts in monocyte-derived macrophages. High levels of MEF2A–MEF2D heterodimers are found in macrophage-differentiated HL60 cells. Chromatin immunoprecipitations demonstrate that MEF2A is present on the c-Jun promoter, both in undifferentiated and in macrophage-differentiated cells. Moreover, c-Jun expression is derepressed in undifferentiated cells in the presence of HDAC (histone deacetylase) inhibitor, indicating the importance of chromatin acetylation in this process. We show that MEF2A/D dimers strongly interact with HDAC1, and to a lesser extent with HDAC7 in macrophages, whereas low levels of MEF2A/D–HDAC1 complexes are found in undifferentiated cells or in monocytes. Since trichostatin A does not disrupt MEF2A/D–HDAC1 complexes, we analysed the potential interaction of MEF2A with p300 histone acetyltransferase, whose expression is up-regulated in macrophages. Interestingly, endogenous p300 only associates with MEF2A in differentiated macrophages, indicating that MEF2A/D could activate c-Jun expression in macrophages through a MEF2A/D–p300 activator complex. The targets of MEF2A/D–HDAC1–HDAC7 multimers remain to be identified. Nevertheless, these data highlight for the first time the possible dual roles of MEF2A and MEF2D in human macrophages, as activators or as repressors of gene transcription.
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Xia, Xin, Caroline Y. Yu, Minjuan Bian, Catalina B. Sun, Bogdan Tanasa, Kun-Che Chang, Dawn M. Bruffett, et al. "MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury." PLOS ONE 15, no. 12 (December 14, 2020): e0242884. http://dx.doi.org/10.1371/journal.pone.0242884.
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Loss of retinal ganglion cells (RGCs) in optic neuropathies results in permanent partial or complete blindness. Myocyte enhancer factor 2 (MEF2) transcription factors have been shown to play a pivotal role in neuronal systems, and in particular MEF2A knockout was shown to enhance RGC survival after optic nerve crush injury. Here we expanded these prior data to study bi-allelic, tri-allelic and heterozygous allele deletion. We observed that deletion of all MEF2A, MEF2C, and MEF2D alleles had no effect on RGC survival during development. Our extended experiments suggest that the majority of the neuroprotective effect was conferred by complete deletion of MEF2A but that MEF2D knockout, although not sufficient to increase RGC survival on its own, increased the positive effect of MEF2A knockout. Conversely, MEF2A over-expression in wildtype mice worsened RGC survival after optic nerve crush. Interestingly, MEF2 transcription factors are regulated by post-translational modification, including by calcineurin-catalyzed dephosphorylation of MEF2A Ser-408 known to increase MEF2A-dependent transactivation in neurons. However, neither phospho-mimetic nor phospho-ablative mutation of MEF2A Ser-408 affected the ability of MEF2A to promote RGC death in vivo after optic nerve injury. Together these findings demonstrate that MEF2 gene expression opposes RGC survival following axon injury in a complex hierarchy, and further support the hypothesis that loss of or interference with MEF2A expression might be beneficial for RGC neuroprotection in diseases such as glaucoma and other optic neuropathies.
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Zhang, Pengcheng, Lianzhong Zhao, Shaowei Qiu, Ravi Bhatia, and Rui Lu. "Essential Roles of Transcription Factor MEF2D in the Maintenance of MLL-Rearranged Acute Myeloid Leukemia." Blood 138, Supplement 1 (November 5, 2021): 2218. http://dx.doi.org/10.1182/blood-2021-149232.
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Abstract Acute myeloid leukemia (AML) is an aggressive disease with uncontrolled proliferation of myeloid progenitor cells and a failure of proper cell differentiation. Chromosomal translocations of the KMT2A (MLL) gene are found in about 10% AMLs affecting both children and adults. Patients harboring MLL rearrangement (MLL-r) have a high relapse rate and poor overall survival, emphasizing an unmet need to understand MLL-r AML pathogenesis and develop new therapeutic means. Through a comparative analysis of super-enhancers in AML cell lines and primary samples, we discovered that MLL-r leukemia cells preferentially gain super-enhancer signals at the MEF2D gene. MEF2D is aberrantly activated in MLL-r AML patient samples and predicts poor disease outcomes, implying a potential oncogenic role of MEF2D. Indeed, depletion of MEF2D inhibits human MLL-r leukemia growth and induces profound differentiation. Mechanistically, MEF2D directly represses CEBPE, a master regulator of myeloid differentiation. CEBPE depletion could rescue the growth defect and cell differentiation induced by MEF2D loss. We also demonstrated that MEF2D is positively regulated by HOXA9, and downregulation of MEF2D is an important mechanism for DOT1L inhibitor-induced anti-leukemia effects. Interestingly, MEF2C, a target of MLL fusion oncoproteins, is by far the most studied MEF2 family member with essential roles in MLL-r AML. Our genetic, biochemical, and integrative genomic data shows that MEF2D and MEF2C, both upregulated in MLL-r AML, interact with each other, colocalize genome-widely, and co-regulate target gene expression. We are currently investigating the molecular mechanisms underlying the interdependent function between MEF2 paralogs in MLL-r AML. Collectively, our findings suggest that MEF2D is a novel transcriptional dependency in MLL-r AML and uncover the MEF2-CEBPE axis as a crucial transcriptional mechanism regulating leukemia cell self-renewal and differentiation block. Disclosures No relevant conflicts of interest to declare.
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Han, T. H., and R. Prywes. "Regulatory role of MEF2D in serum induction of the c-jun promoter." Molecular and Cellular Biology 15, no. 6 (June 1995): 2907–15. http://dx.doi.org/10.1128/mcb.15.6.2907.
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Serum induction of c-jun expression in HeLa cells requires a MEF2 site at -59 in the c-jun promoter. MEF2 sites, found in many muscle-specific enhancers, are bound by a family of transcription factors, MEF2A through -D, which are related to serum response factor in their DNA binding domains. We have found that MEF2D is the predominant protein in HeLa cells that binds to the c-jun MEF2 site. Serum induction of a MEF2 reporter gene was not observed in a line of NIH 3T3 cells which contain low MEF2 site binding activity. Transfection of MEF2D into NIH 3T3 cells reconstituted serum induction, demonstrating that MEF2D is required for the serum response. Deletion analysis of MEF2D showed that its DNA binding domain, when fused to a heterologous transcriptional activation domain, was sufficient for serum induction of a MEF2 reporter gene. This is the domain homologous to that in the serum response factor which is required for serum induction of the c-fos serum response element, suggesting that serum regulation of c-fos and c-jun may share a common mechanism.
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Potthoff, Matthew J., Michael A. Arnold, John McAnally, James A. Richardson, Rhonda Bassel-Duby, and Eric N. Olson. "Regulation of Skeletal Muscle Sarcomere Integrity and Postnatal Muscle Function by Mef2c." Molecular and Cellular Biology 27, no. 23 (September 17, 2007): 8143–51. http://dx.doi.org/10.1128/mcb.01187-07.
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ABSTRACT Myocyte enhancer factor 2 (MEF2) transcription factors cooperate with the MyoD family of basic helix-loop-helix (bHLH) transcription factors to drive skeletal muscle development during embryogenesis, but little is known about the potential functions of MEF2 factors in postnatal skeletal muscle. Here we show that skeletal muscle-specific deletion of Mef2c in mice results in disorganized myofibers and perinatal lethality. In contrast, neither Mef2a nor Mef2d is required for normal skeletal muscle development in vivo. Skeletal muscle deficient in Mef2c differentiates and forms normal myofibers during embryogenesis, but myofibers rapidly deteriorate after birth due to disorganized sarcomeres and a loss of integrity of the M line. Microarray analysis of Mef2c null muscles identified several muscle structural genes that depend on MEF2C, including those encoding the M-line-specific proteins myomesin and M protein. We show that MEF2C directly regulates myomesin gene transcription and that loss of Mef2c in skeletal muscle results in improper sarcomere organization. These results reveal a key role for Mef2c in maintenance of sarcomere integrity and postnatal maturation of skeletal muscle.
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Vissing, Kristian, Sean L. McGee, Carsten Roepstorff, Peter Schjerling, Mark Hargreaves, and Bente Kiens. "Effect of sex differences on human MEF2 regulation during endurance exercise." American Journal of Physiology-Endocrinology and Metabolism 294, no. 2 (February 2008): E408—E415. http://dx.doi.org/10.1152/ajpendo.00403.2007.
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Women exhibit an enhanced capability for lipid metabolism during endurance exercise compared with men. The underlying regulatory mechanisms behind this sex-related difference are not well understood but may comprise signaling through a myocyte enhancer factor 2 (MEF2) regulatory pathway. The primary purpose of this study, therefore, was to investigate the protein signaling of MEF2 regulatory pathway components at rest and during 90 min of bicycling exercise at 60% V̇o2peak in healthy, moderately trained men ( n = 8) and women ( n = 9) to elucidate the potential role of these proteins in substrate utilization during exercise. A secondary purpose was to screen for mRNA expression of MEF2 isoforms and myogenic regulatory factor (MRF) family members of transcription factors at rest and during exercise. Muscle biopsies were obtained before and immediately after exercise. Nuclear AMP-activated protein kinase-α (αAMPK) Thr172 ( P < 0.001), histone deacetylase 5 (HDAC5) Ser498 ( P < 0.001), and MEF2 Thr ( P < 0.01) phosphorylation increased with exercise. No significant sex differences were observed at rest or during exercise. At rest, no significant sex differences were observed in mRNA expression of the measured transcription factors. mRNA for transcription factors MyoD, myogenin, MRF4, MEF2A, MEF2C, MEF2D, and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) were significantly upregulated by exercise. Of these, MEF2A mRNA increased 25% specifically in women ( P < 0.05), whereas MEF2D mRNA tended to increase in men ( P = 0.11). Although minor sex differences in mRNA expression were observed, the main finding of the present study was the implication of a joint signaling action of AMPK, HDAC5, and PGC1α on MEF2 in the immediate regulatory response to endurance exercise. This signaling response was independent of sex.
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Du, Min, Robert L. S. Perry, Nathaniel B. Nowacki, Joseph W. Gordon, Jahan Salma, Jianzhong Zhao, Arif Aziz, Joseph Chan, K. W. Michael Siu, and John C. McDermott. "Protein Kinase A Represses Skeletal Myogenesis by Targeting Myocyte Enhancer Factor 2D." Molecular and Cellular Biology 28, no. 9 (February 25, 2008): 2952–70. http://dx.doi.org/10.1128/mcb.00248-08.
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ABSTRACT Activation of protein kinase A (PKA) by elevation of the intracellular cyclic AMP (cAMP) level inhibits skeletal myogenesis. Previously, an indirect modulation of the myogenic regulatory factors (MRFs) was implicated as the mechanism. Because myocyte enhancer factor 2 (MEF2) proteins are key regulators of myogenesis and obligatory partners for the MRFs, here we assessed whether these proteins could be involved in PKA-mediated myogenic repression. Initially, in silico analysis revealed several consensus PKA phosphoacceptor sites on MEF2, and subsequent analysis by in vitro kinase assays indicated that PKA directly and efficiently phosphorylates MEF2D. Using mass spectrometric determination of phosphorylated residues, we document that MEF2D serine 121 and serine 190 are targeted by PKA. Transcriptional reporter gene assays to assess MEF2D function revealed that PKA potently represses the transactivation properties of MEF2D. Furthermore, engineered mutation of MEF2D PKA phosphoacceptor sites (serines 121 and 190 to alanine) rendered a PKA-resistant MEF2D protein, which efficiently rescues myogenesis from PKA-mediated repression. Concomitantly, increased intracellular cAMP-mediated PKA activation also resulted in an enhanced nuclear accumulation of histone deacetylase 4 (HDAC4) and a subsequent increase in the MEF2D-HDAC4 repressor complex. Collectively, these data identify MEF2D as a primary target of PKA signaling in myoblasts that leads to inhibition of the skeletal muscle differentiation program.
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Ojuka, Edward O., Terry E. Jones, Lorraine A. Nolte, May Chen, Brian R. Wamhoff, Michael Sturek, and John O. Holloszy. "Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca2+." American Journal of Physiology-Endocrinology and Metabolism 282, no. 5 (May 1, 2002): E1008—E1013. http://dx.doi.org/10.1152/ajpendo.00512.2001.
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There is evidence suggesting that adaptive increases in GLUT4 and mitochondria in skeletal muscle occur in parallel. It has been reported that raising cytosolic Ca2+ in myocytes induces increases in mitochondrial enzymes. In this study, we tested the hypothesis that an increase in cytosolic Ca2+ induces an increase in GLUT4. We found that raising cytosolic Ca2+ by exposing L6 myotubes to 5 mM caffeine for 3 h/day for 5 days induced increases in GLUT4 protein and in myocyte enhancer factor (MEF)2A and MEF2D, which are transcription factors involved in regulating GLUT4 expression. The caffeine-induced increases in GLUT4 and MEF2A and MEF2D were partially blocked by dantrolene, an inhibitor of sarcoplasmic reticulum Ca2+ release, and completely blocked by KN93, an inhibitor of Ca2+-calmodulin-dependent protein kinase (CAMK). Caffeine also induced increases in MEF2A, MEF2D, and GLUT4 in rat epitrochlearis muscles incubated with caffeine in culture medium. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR), which activates AMP-activated protein kinase (AMPK), also induced approximately twofold increases in GLUT4, MEF2A, and MEF2D in L6 myocytes. Our results provide evidence that increases in cytosolic Ca2+and activation of AMPK, both of which occur in exercising muscle, increase GLUT4 protein in myocytes and skeletal muscle. The data suggest that this effect of Ca2+ is mediated by activation of CAMK and indicate that MEF2A and MEF2D are involved in this adaptive response.
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Prima, Victor, Lia Gore, Aimee Caires, Theresa Boomer, Miyako Yoshinari, Imaizume Masue, Varella-Garcia Marileila, and Stephen P. Hunger. "Chimeric MEF2D and Dazap1 Fusion Proteins Are Created by a Variant t(1;19)(q23;p13.3) in Acute Lymphoblastic Leukemia (ALL)." Blood 104, no. 11 (November 16, 2004): 548. http://dx.doi.org/10.1182/blood.v104.11.548.548.
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Abstract The t(1;19)(q23;p13) is one of the most common chromosome translocations in ALL. In 90–95% of ALL cases with a t(1;19), the 19p13.3 gene E2A is fused to PBX1 located at 1q23, producing E2A-PBX1 chimeric proteins that possess transforming properties. The molecular abnormalities present in the 5–10% of ALL cases with a t(1;19) but no E2A-PBX1 fusion are unknown. TS-2 is an ALL cell line with a t(1;19)(q23;p13.3) but no E2A-PBX1 fusion. We used fluoresence in situ hybridization to localize the chromosome 19 breakpoint in TS-2 to a region approximately 400 kilobases telomeric to E2A and found that the t(1;19) in TS-2 fuses the 19p13 gene DAZAP1 (deleted in azoospermia associated protein 1) to the 1q23 gene MEF2D (myocte enhancer factor 2D). We cloned and sequenced the fusion genes and found they encode for reciprocal in-frame DAZAP1/MEF2D and MEF2D/DAZAP1 fusion transcripts, both of which are expressed in TS-2. MEF2D is a member of the MEF2 family of DNA binding proteins, which were originally characterized as muscle-specific transcription factors that regulated transcription of genes involved in myogenic differentiation. MEF2 proteins are now recognized to have more diverse functions: they are transcriptional effectors of mitogenic signaling pathways and inflammation, play critical roles in calcium-regulated signaling pathways that mediate survival of neurons and T-lympocytes, and participate in neuronal plasticity. DAZAP1 is a protein with novel RNA binding properties that is expressed most abundantly in testis and to a lesser extent in thymus. MEF2D-DAZAP1 includes the MEF2D MADS (MCM1, agamous, deficiens, and serum response factor) box and adjacent MEF2D domain that mediate sequence-specific DNA binding and protein-protein interactions, as well as one of two MEF2D transcriptional activation domains (TAD) fused to the C-terminus of DAZAP1. The DAZAP1-MEF2D chimera includes an intact first and truncated second RNA recognition motif from DAZAP1 joined to the C-terminus of MEF2D that includes its second TAD. We performed electrophoretic mobility shift assays using cognate and mutant MEF2D DNA recognition sites and found that MEF2D/DAZAP1 binds avidly and specifically to DNA in a manner indistinguishable from that of native MEF2D. We found that MEF2D/DAZAP1 activated transcription of a luciferase reporter gene under control of MEF2D recognition elements with substantially more potency than did wild type MEF2D. We also show that DAZAP1/MEF2D proteins bind RNA in a sequence specific manner analogous to that of wild type DAZAP1. MEF2D has been identified as a candidate oncogene involved in development of leukemia/lymphoma via murine retroviral insertional mutagenesis studies. Our data implicate MEF2D in human cancer and suggest that MEF2D/DAZAP1 and/or DAZAP1/MEF2D contributes to leukemogenesis by altering signaling pathways normally regulated by wild type MEF2D and DAZAP1.
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Liao, Shengfa F., Zhongyue Yang, M. Shamimul Hasan, Rebecca Humphrey, Jean Feugang, Derris Burnett, and John K. Htoo. "200 Reduced growth performance of pigs fed methionine deficient diet may be associated with their reduced muscle cell differentiation." Journal of Animal Science 98, Supplement_3 (November 2, 2020): 70. http://dx.doi.org/10.1093/jas/skaa054.125.
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Abstract Methionine (Met) is the second or third limiting AA in typical swine diets and plays important roles in promoting the growth, especially, the muscle growth of pigs. This research studied the effects of dietary Met restriction on growth performance and myogenic gene expression in growing pigs. Eight genes in two families, including myogenic regulatory factor family comprising myogenic differentiation 1 (MyoD1), myogenic factor 5 (Myf5), myogenin (MyoG) and myogenic factor 6 (Myf6), and myocyte enhancer factor 2 (Mef2) family comprising Mef2A, Mef2B, Mef2C and Mef2D, were selected for analysis. Individually penned barrows (crossbred, 23.6±2.4 kg) were randomly assigned to two dietary treatments. A basal diet (Diet 1; Met-deficient) was formulated to contain 0.22% standardized ileal digestible (SID) Met and 0.52% SID Met+Cys but to meet the NRC (2012) recommendations for other nutrients. Crystalline DL-Met was added to the basal diet to generate Diet 2 adequate in Met (0.37% SID Met, 0.67% SID Met+Cys). During the four-week ad libitum feeding trial, ADG, ADFI and G:F were measured. Immediately before and after the trial, muscle samples were collected from the longissimus dorsi using a standard biopsy protocol. Total RNA was extracted from the muscle samples (TRIzol Reagent; Invitrogen) and subjected to cDNA reverse-transcription (QuantiTect Reverse Transcription Kit; Qiagen). Transcribed cDNA were used for qPCR analysis (Rotor-Gene Q System; Qiagen). Comparative ΔΔCT method was used for quantitation. Data were analyzed with Student’s T-test. Pigs fed Diet 1 (vs. Diet 2) had a lower ADG and G:F (P< 0.01). Before the feeding trial, all the tested genes had comparable mRNA levels between the two treatments (P >0.17). After the trial, Diet 1 pigs showed tendency for lower levels of Myf6 and Mef2D mRNA (P< 0.09). These results suggest that the reduced ADG and G:F is associated with the possibly-reduced muscle cell differentiation in pigs fed Met-deficient diet.
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Ouyang, Hongjia, Jiao Yu, Xiaolan Chen, Zhijun Wang, and Qinghua Nie. "A novel transcript of MEF2D promotes myoblast differentiation and its variations associated with growth traits in chicken." PeerJ 8 (February 4, 2020): e8351. http://dx.doi.org/10.7717/peerj.8351.
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Background Development of skeletal muscle is closely related to broiler production traits. The myocyte-specific enhancer binding factor (MEF) 2D gene (MEF2D) and its variant transcripts play important parts in myogenesis. Methods To identify the transcript variants of chicken MEF2D gene and their function, this study cloned chicken MEF2D gene and identified its transcript variants from different tissue samples. The expression levels of different transcripts of MEF2D gene in different tissues and different periods were measured, and their effects on myoblast proliferation and differentiation were investigated. Variations in MEF2D were identified and association analysis with chicken production traits carried out. Results Four novel transcript variants of MEF2D were obtained, all of which contained highly conserved sequences, including MADS-Box and MEF2-Domain functional regions. Transcript MEF2D-V4 was expressed specifically in muscle, and its expression was increased during embryonic muscle development. The MEF2D-V4 could promote differentiation of chicken myoblasts and its expression was regulated by RBFOX2. The single nucleotide polymorphism g.36186C > T generated a TAG stop codon, caused MEF2D-V4 to terminate translation early, and was associated with several growth traits, especially on early body weight. Conclusion We cloned the muscle-specific transcript of MEF2D and preliminarily revealed its role in embryonic muscle development.
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Breitbart, R. E., C. S. Liang, L. B. Smoot, D. A. Laheru, V. Mahdavi, and B. Nadal-Ginard. "A fourth human MEF2 transcription factor, hMEF2D, is an early marker of the myogenic lineage." Development 118, no. 4 (August 1, 1993): 1095–106. http://dx.doi.org/10.1242/dev.118.4.1095.
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The transition from multipotent mesodermal precursor to committed myoblast and its differentiation into a mature myocyte involve molecular events that enable the cell to activate muscle-specific genes. Among the participants in this process is the myocyte-specific enhancer factor 2 (MEF2) family of tissue-restricted transcription factors. These factors, which share a highly conserved DNA-binding domain including a MADS box, are essential for the expression of multiple muscle genes with cognate target MEF2 sites in cis. We report here a new human MEF2 factor, hMEF2D, which is unique among the members of this family in that it is present not only in myotubes but also in undifferentiated myoblasts, even before the appearance of myogenin. hMEF2D comprises several alternatively spliced products of a single gene, one of which is the human homolog of the Xenopus SRF-related factor SL-1. Like its relatives, cloned hMEF2D is capable of activating transcription via sequence-specific binding to the MEF2 site, recapitulating endogenous tissue-specific MEF2 activity. Indeed, while MEF2D mRNAs are ubiquitous, the protein is highly restricted to those cell types that contain this activity, implicating posttranscriptional mechanisms in the regulation of MEF2D expression. Alternative splicing may be important in this process: two alternative MEF2D domains, at least one of which is specifically included during myogenic differentiation, also correlate precisely with endogenous MEF2 activity. These findings provide compelling evidence that MEF2D is an integral link in the regulatory network for muscle gene expression. Its presence in undifferentiated myoblasts further suggests that it may be a mediator of commitment in the myogenic lineage.
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Di Giorgio, Eros, Emiliano Dalla, Elisa Franforte, Harikrishnareddy Paluvai, Martina Minisini, Matteo Trevisanut, Raffaella Picco, and Claudio Brancolini. "Different class IIa HDACs repressive complexes regulate specific epigenetic responses related to cell survival in leiomyosarcoma cells." Nucleic Acids Research 48, no. 2 (November 22, 2019): 646–64. http://dx.doi.org/10.1093/nar/gkz1120.
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Abstract Transcriptional networks supervising class IIa HDAC expression are poorly defined. Here we demonstrate that MEF2D is the key factor controlling HDAC9 transcription. This control, which is part of a negative feed-back loop during muscle differentiation, is hijacked in cancer. In leiomyosarcomas the MEF2D/HDAC9 vicious circuit sustains proliferation and cell survival, through the repression of the death receptor FAS. Comprehensive genome-wide studies demonstrate that HDAC4 and HDAC9 control different genetic programs and show both specific and common genomic binding sites. Although the number of MEF2-target genes commonly regulated is similar, only HDAC4 represses many additional genes that are not MEF2D targets. As expected, HDAC4−/− and HDAC9−/− cells increase H3K27ac levels around the TSS of the respective repressed genes. However, these genes rarely show binding of the HDACs at their promoters. Frequently HDAC4 and HDAC9 bind intergenic regions. We demonstrate that these regions, recognized by MEF2D/HDAC4/HDAC9 repressive complexes, show the features of active enhancers. In these regions HDAC4 and HDAC9 can differentially influence H3K27 acetylation. Our studies describe new layers of class IIa HDACs regulation, including a dominant positional effect, and can contribute to explain the pleiotropic actions of MEF2 TFs.
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Kasler, Herbert G., Joseph Victoria, Omar Duramad, and Astar Winoto. "ERK5 Is a Novel Type of Mitogen-Activated Protein Kinase Containing a Transcriptional Activation Domain." Molecular and Cellular Biology 20, no. 22 (November 15, 2000): 8382–89. http://dx.doi.org/10.1128/mcb.20.22.8382-8389.2000.
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ABSTRACT Previous studies have shown that upregulation of the orphan steroid receptor Nur77 is required for the apoptosis of immature T cells in response to antigen receptor signals. Transcriptional upregulation of Nur77 in response to antigen receptor signaling involves two binding sites for the MEF2 family of transcription factors located in the Nur77 promoter. Calcium signals greatly increase the activity of MEF2D in T cells via a posttranslational mechanism. The mitogen-activated protein (MAP) kinase ERK5 was isolated in a yeast two-hybrid screen using the MADS-MEF2 domain of MEF2D as bait. ERK5 resembles the other MAP kinase family members in its N-terminal half, but it also contains a 400-amino-acid C-terminal domain of previously uncharacterized function. We report here that the C-terminal region of ERK5 contains a MEF2-interacting domain and, surprisingly, also a potent transcriptional activation domain. These domains are both required for coactivation of MEF2D by ERK5. The MEF2-ERK5 interaction was found to be activation dependent in vivo and inhibitable in vitro by the calcium-sensitive MEF2 repressor Cabin 1. The transcriptional activation domain of ERK5 is required for maximal MEF2 activity in response to calcium flux in T cells, and it can activate the endogenous Nur77 gene when constitutively recruited to the Nur77 promoter via MEF2 sites. These studies provide insights into a mechanism whereby MEF2 activity can respond to calcium signaling and suggest a novel, unexpected mechanism of MAP kinase function.
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Harada, Taku, Yaser Heshmati, Jérémie Kalfon, Monika W. Perez, Juliana Xavier Ferrucio, Jazmin Ewers, Benjamin Hubbell Engler, et al. "A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia." Genes & Development 36, no. 5-6 (March 1, 2022): 368–89. http://dx.doi.org/10.1101/gad.349284.121.
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Acute myeloid leukemia with KMT2A (MLL) rearrangements is characterized by specific patterns of gene expression and enhancer architecture, implying unique core transcriptional regulatory circuitry. Here, we identified the transcription factors MEF2D and IRF8 as selective transcriptional dependencies of KMT2A-rearranged AML, where MEF2D displays partially redundant functions with its paralog, MEF2C. Rapid transcription factor degradation followed by measurements of genome-wide transcription rates and superresolution microscopy revealed that MEF2D and IRF8 form a distinct core regulatory module with a narrow direct transcriptional program that includes activation of the key oncogenes MYC, HOXA9, and BCL2. Our study illustrates a mechanism of context-specific transcriptional addiction whereby a specific AML subclass depends on a highly specialized core regulatory module to directly enforce expression of common leukemia oncogenes.
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Grégoire, Serge, Lin Xiao, Jianyun Nie, Xiaohong Zhang, Minghong Xu, Jiarong Li, Jiemin Wong, Edward Seto, and Xiang-Jiao Yang. "Histone Deacetylase 3 Interacts with and Deacetylates Myocyte Enhancer Factor 2." Molecular and Cellular Biology 27, no. 4 (December 11, 2006): 1280–95. http://dx.doi.org/10.1128/mcb.00882-06.
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ABSTRACT The myocyte enhancer factor 2 (MEF2) family of transcription factors is not only important for controlling gene expression in normal cellular programs, like muscle differentiation, T-cell apoptosis, neuronal survival, and synaptic differentiation, but has also been linked to cardiac hypertrophy and other pathological conditions. Lysine acetylation has been shown to modulate MEF2 function, but it is not so clear which deacetylase(s) is involved. We report here that treatment of HEK293 cells with trichostatin A or nicotinamide upregulated MEF2D acetylation, suggesting that different deacetylases catalyze the deacetylation. Related to the trichostatin A sensitivity, histone deacetylase 4 (HDAC4) and HDAC5, two known partners of MEF2, exhibited little deacetylase activity towards MEF2D. In contrast, HDAC3 efficiently deacetylated MEF2D in vitro and in vivo. This was specific, since HDAC1, HDAC2, and HDAC8 failed to do so. While HDAC4, HDAC5, HDAC7, and HDAC9 are known to recognize primarily the MEF2-specific domain, we found that HDAC3 interacts directly with the MADS box. In addition, HDAC3 associated with the acetyltransferases p300 and p300/CBP-associated factor (PCAF) to reverse autoacetylation. Furthermore, the nuclear receptor corepressor SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) stimulated the deacetylase activity of HDAC3 towards MEF2 and PCAF. Supporting the physical interaction and deacetylase activity, HDAC3 repressed MEF2-dependent transcription and inhibited myogenesis. These results reveal an unexpected role for HDAC3 and suggest a novel pathway through which MEF2 activity is controlled in vivo.
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Herglotz, Julia, Ludmilla Unrau, Friderike Hauschildt, Meike Fischer, Neele Kriebitzsch, Malik Alawi, Daniela Indenbirken, et al. "Essential control of early B-cell development by Mef2 transcription factors." Blood 127, no. 5 (February 4, 2016): 572–81. http://dx.doi.org/10.1182/blood-2015-04-643270.
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Key Points Mef2c and Mef2d are activated by the pre-B-cell receptor and are essential for pre-B-cell transition. Mef2c complexes with B-cell transcription factors to shut down the immediate early response and to initiate a new transcriptional network.
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Ju, Jeong-Sun, Jill L. Smith, Peter J. Oppelt, and Jonathan S. Fisher. "Creatine feeding increases GLUT4 expression in rat skeletal muscle." American Journal of Physiology-Endocrinology and Metabolism 288, no. 2 (February 2005): E347—E352. http://dx.doi.org/10.1152/ajpendo.00238.2004.
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The purpose of this study was to investigate the potential role of creatine in GLUT4 gene expression in rat skeletal muscle. Female Wistar rats were fed normal rat chow (controls) or chow containing 2% creatine monohydrate ad libitum for 3 wk. GLUT4 protein levels of creatine-fed rats were significantly increased in extensor digitorum longus (EDL), triceps, and epitrochlearis muscles compared with muscles from controls ( P < 0.05), and triceps GLUT4 mRNA levels were ∼100% greater in triceps muscles from creatine-fed rats than in muscles from controls ( P < 0.05). In epitrochlearis muscles from creatine-fed animals, glycogen content was ∼40% greater ( P < 0.05), and insulin-stimulated glucose transport rates were higher ( P < 0.05) than in epitrochlearis muscles from controls. Despite no changes in [ATP], [creatine], [phosphocreatine], or [AMP], creatine feeding increased AMP-activated protein kinase (AMPK) phosphorylation by 50% in rat EDL muscle ( P < 0.05). Creatinine content of EDL muscle was almost twofold higher for creatine-fed animals than for controls ( P < 0.05). Creatine feeding increased protein levels of myocyte enhancer factor 2 (MEF2) isoforms MEF2A (∼70%, P < 0.05), MEF2C (∼60%, P < 0.05), and MEF2D (∼90%, P < 0.05), which are transcription factors that regulate GLUT4 expression, in creatine-fed rat EDL muscle nuclear extracts. Electrophoretic mobility shift assay showed that DNA binding activity of MEF2 was increased by ∼40% ( P < 0.05) in creatine-fed rat EDL compared with controls. Our data suggest that creatine feeding enhances the nuclear content and DNA binding activity of MEF2 isoforms, which is concomitant with an increase in GLUT4 gene expression.
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Grégoire, Serge, and Xiang-Jiao Yang. "Association with Class IIa Histone Deacetylases Upregulates the Sumoylation of MEF2 Transcription Factors." Molecular and Cellular Biology 25, no. 6 (March 15, 2005): 2273–87. http://dx.doi.org/10.1128/mcb.25.6.2273-2287.2005.
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ABSTRACT The myocyte enhancer factor-2 (MEF2) family of transcription factors plays an important role in regulating cellular programs like muscle differentiation, neuronal survival, and T-cell apoptosis. Multisite phosphorylation is known to control the transcriptional activity of MEF2 proteins, but it is unclear whether other modifications are involved. Here, we report that human MEF2D, as well as MEF2C, is modified by SUMO2 and SUMO3 at a motif highly conserved among MEF2 proteins from diverse organisms. This motif is located within the C-terminal transcriptional activation domain, and its sumoylation inhibits transcription. As a transcriptional corepressor of MEF2, histone deacetylase 4 (HDAC4) potentiates sumoylation. This potentiation is dependent on the N-terminal region but not the C-terminal deacetylase domain of HDAC4 and is inhibited by the sumoylation of HDAC4 itself. Moreover, HDAC5, HDAC7, and an HDAC9 isoform also stimulate sumoylation of MEF2. Opposing the action of class IIa deacetylases, the SUMO protease SENP3 reverses the sumoylation to augment the transcriptional and myogenic activities of MEF2. Similarly, the calcium M kinase and extracellular signal-regulated kinase 5 signaling pathways negatively regulate the sumoylation. These results thus identify sumoylation as a novel regulatory mechanism for MEF2 and suggest that this modification interplays with phosphorylation to promote intramolecular signaling for coordinated regulation in vivo.
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Zhao, Lianzhong, Pengcheng Zhang, Phillip M. Galbo, Xinyue Zhou, Sajesan Aryal, Shaowei Qiu, Hao Zhang, et al. "Transcription factor MEF2D is required for the maintenance of MLL-rearranged acute myeloid leukemia." Blood Advances 5, no. 22 (November 22, 2021): 4727–40. http://dx.doi.org/10.1182/bloodadvances.2021004469.
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Abstract Acute myeloid leukemia (AML) with MLL-rearrangement (MLL-r) comprises ∼10% of all AML cases and portends poor outcomes. Much remains uncovered on how MLL-r AML drives leukemia development while preventing cells from normal myeloid differentiation. Here, we identified that transcription factor MEF2D is a super-enhancer-associated, highly expressed gene in MLL-r AML. Knockout of MEF2D profoundly impaired leukemia growth, induced myeloid differentiation, and delayed oncogenic progression in vivo. Mechanistically, MEF2D loss led to robust activation of a CEBPE-centered myeloid differentiation program in AML cells. Chromatin profiling revealed that MEF2D binds to and suppresses the chromatin accessibility of CEBPE cis-regulatory regions. In human acute leukemia samples, MEF2D expression showed a strong negative correlation with the expression of CEBPE. Depletion of CEBPE partially rescued the cell growth defect and myeloid cell differentiation induced by the loss of MEF2D. Lastly, we show that MEF2D is positively regulated by HOXA9, and downregulation of MEF2D is an important mechanism for DOT1L inhibitor-induced antileukemia effects. Collectively, our findings suggest that MEF2D plays a critical role in human MLL-r AML and uncover the MEF2D-CEBPE axis as a crucial transcriptional mechanism regulating leukemia cell self-renewal and differentiation block.
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Bai, Jianfeng, Qingqing Yu, and Tongbo Ning. "Up-regulation of miR-30b suppresses glioblastoma by negatively regulating MEF2D through Wnt/β-catenin signaling pathway." Tropical Journal of Pharmaceutical Research 20, no. 7 (February 9, 2022): 1325–30. http://dx.doi.org/10.4314/tjpr.v20i7.1.
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Purpose: To study miR-30b’ significance on glioblastoma, and its underlying mechanism of action.
Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) while 3-(4,5)- dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT), Transwell, and xenograft tumor formation assays were carried out to study miR-30b’s effect on glioblastoma while luciferase reporter assay was employed to study the interaction between MEF2D and miR-30b. Glioblastoma cells treatment with miR-30 mimic or inhibitor were subjected to Western blot assay to study the effect of Wnt/β-catenin signaling on miR-30b/MEF2D axis-mediated cell progression.
Results: MiR-30b was lowly expressed in glioblastoma tissues (p = 0.007), and this was associated with poor prognosis of patients (p = 0.022). The direct target of miR-30b was identified as MEF2D (p = 0.036). Increasing miR-30b blocked MEF2D expression in glioblastoma cells (p = 0.029). Moreover, MEF2D overturned miR-30b’ inhibitory effect on glioblastoma cell progression (p = 0.041; p = 0.006; p = 0.037). In vivo, restoration of miR-30b inhibited tumor growth (p = 0.01) and MEF2D. Interestingly, restoration of miR-30b inhibited epithelial-to-mesenchymal transition (EMT) and Wnt/β-catenin signaling pathways.
Conclusion: These results indicate the critical role of miR-30b/MEF2D axis in glioblastoma via EMT and Wnt/β-catenin pathways. Thus, the miR-30b/MEF2D axis might be a beneficial therapeutic target for the management of glioblastoma patients.
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Arosio, Alessandro, Gessica Sala, Virginia Rodriguez-Menendez, Denise Grana, Francesca Gerardi, Christian Lunetta, Carlo Ferrarese, and Lucio Tremolizzo. "MEF2D and MEF2C pathways disruption in sporadic and familial ALS patients." Molecular and Cellular Neuroscience 74 (July 2016): 10–17. http://dx.doi.org/10.1016/j.mcn.2016.02.002.
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Molkentin, J. D., A. B. Firulli, B. L. Black, J. F. Martin, C. M. Hustad, N. Copeland, N. Jenkins, G. Lyons, and E. N. Olson. "MEF2B is a potent transactivator expressed in early myogenic lineages." Molecular and Cellular Biology 16, no. 7 (July 1996): 3814–24. http://dx.doi.org/10.1128/mcb.16.7.3814.
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There are four members of the myocyte enhancer binding factor 2 (MEF2) family of transcription factors, MEF2A, -B, -C, and -D, that have homology within an amino-terminal MADS box and an adjacent MEF2 domain that together mediate dimerization and DNA binding. MEF2A, -C, and -D have previously been shown to bind an A/T-rich DNA sequence in the control regions of numerous muscle-specific genes, whereas MEF2B was reported to be unable to bind this sequence unless the carboxyl terminus was deleted. To further define the functions of MEF2B, we analyzed its DNA binding and transcriptional activities. In contrast to previous studies, our results show that MEF2B binds the same DNA sequence as other members of the MEF2 family and acts as a strong transactivator through that sequence. Transcriptional activation by MEF2B is dependent on the carboxyl terminus, which contains two conserved sequence motifs found in all vertebrate MEF2 factors. During mouse embryogenesis, MEF2B transcripts are expressed in the developing cardiac and skeletal muscle lineages in a temporospatial pattern distinct from but overlapping with those of the other Mef2 genes. The mouse Mef2b gene maps to chromosome 8 and is unlinked to other Mef2 genes; its intron-exon organization is similar to that of the other vertebrate Mef2 genes and the single Drosophila Mef2 gene, consistent with the notion that these different Mef2 genes evolved from a common ancestral gene.
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Novakova, Katerina, Michael Török, Miljenko Panajatovic, Jamal Bouitbir, François H. T. Duong, Christoph Handschin, and Stephan Krähenbühl. "PGC-1α and MEF2 Regulate the Transcription of the Carnitine Transporter OCTN2 Gene in C2C12 Cells and in Mouse Skeletal Muscle." International Journal of Molecular Sciences 23, no. 20 (October 14, 2022): 12304. http://dx.doi.org/10.3390/ijms232012304.
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OCTN2 (SLC22A5) is a carnitine transporter whose main function is the active transport of carnitine into cells. In skeletal muscle and other organs, the regulation of the SLC22A5 gene transcription has been shown to depend on the nuclear transcription factor PPAR-α. Due to the observation that the muscle OCTN2 mRNA level is maintained in PPAR-α knock-out mice and that PGC-1α overexpression in C2C12 myoblasts increases OCTN2 mRNA expression, we suspected additional regulatory pathways for SLC22A5 gene transcription. Indeed, we detected several binding sites of the myocyte-enhancing factor MEF2 in the upstream region of the SLC22A5 gene, and MEF2C/MEF2D stimulated the activity of the OCTN2 promoter in gene reporter assays. This stimulation was increased by PGC-1α and was blunted for a SLC22A5 promoter fragment with a mutated MEF2 binding site. Further, we demonstrated the specific binding of MEF2 to the SLC22A5 gene promoter, and a supershift of the MEF2/DNA complex in electrophoretic mobility shift assays. In immunoprecipitation experiments, we could demonstrate the interaction between PGC-1α and MEF2. In addition, SB203580, a specific inhibitor of p38 MAPK, blocked and interferon-γ stimulated the transcriptional activity of the SLC22A5 gene promoter. Finally, mice with muscle-specific overexpression of OCTN2 showed an increase in OCTN2 mRNA and protein expression in skeletal muscle. In conclusion, we detected and characterized a second stimulatory pathway of SLC22A5 gene transcription in skeletal muscle, which involves the nuclear transcription factor MEF2 and co-stimulation by PGC-1α and which is controlled by the p38 MAPK signaling cascade.
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He, Zhou, Ding, Teng, Yan, and Liang. "Common Carp mef2 Genes: Evolution and Expression." Genes 10, no. 8 (August 1, 2019): 588. http://dx.doi.org/10.3390/genes10080588.
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The MEF2 (myocyte enhancer factor 2) family belongs to the MADS-box superfamily of eukaryotic transcription factors. The vertebrate genes compose four distinct subfamilies designated MEF2A, -B, -C, and -D. There are multiple mef2 genes in the common carp (Cyprinus carpio). So far, the embryonic expression patterns of these genes and the evolution of fish mef2 genes have been barely investigated. In this study, we completed the coding information of C. carpio mef2ca2 and mef2d1 genes via gene cloning and presented two mosaic mef2 sequences as evidence for recombination. We also analyzed the phylogenetic relationship and conserved synteny of mef2 genes and proposed a new evolutionary scenario. In our version, MEF2B and the other three vertebrate subfamilies were generated in parallel from the single last ancestor via two rounds of whole genome duplication events that occurred at the dawn of vertebrates. Moreover, we examined the expression patterns of C. carpio mef2 genes during embryogenesis, by using whole-mount in situ hybridization, and found the notochord to be a new expression site for these genes except for mef2ca1&2. Our results thus provide new insights into the evolution and expression of mef2 genes.
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Li, Meihang, Zhenjiang Liu, Zhenzhen Zhang, Guannv Liu, Shiduo Sun, and Chao Sun. "miR-103 promotes 3T3-L1 cell adipogenesis through AKT/mTOR signal pathway with its target being MEF2D." Biological Chemistry 396, no. 3 (March 1, 2015): 235–44. http://dx.doi.org/10.1515/hsz-2014-0241.
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Abstract MicroRNAs are small non-coding RNAs that partially bind to the 3’ untranslated (3’UTR) regions of target genes in animals and regulate protein production of the target transcripts. MiR-103 has been confirmed to play a critical role in lipid metabolism, however, the target genes and signaling pathway regulated by miR-103 is still unclear. In our experiment, we observed a positive function of miR-103 on the adipogenic differentiation of 3T3-L1 pre-adipocyte. Furthermore, we proved that this function of miR-103 worked through activating AKT/mTOR signal pathway and impairing target gene MEF2D. By inhibiting and over-expressing the MEF2D gene, we found that MEF2D had a negative role in regulating adipocyte key genes, and this function of MEF2D could be impaired by miR-103. In conclusion, we found that miR-103 can promote 3T3-L1 cells differentiation by targeting MEF2D and activating AKT/mTOR signal pathway. These results will shed a light on further study of microRNAs.
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Sala, Gessica, Alessandro Arosio, Giovanni Stefanoni, Laura Melchionda, Chiara Riva, Daniele Marinig, Laura Brighina, and Carlo Ferrarese. "Rotenone Upregulates Alpha-Synuclein and Myocyte Enhancer Factor 2D Independently from Lysosomal Degradation Inhibition." BioMed Research International 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/846725.
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Dysfunctions of chaperone-mediated autophagy (CMA), the main catabolic pathway for alpha-synuclein, have been linked to the pathogenesis of Parkinson’s disease (PD). Since till now there is limited information on how PD-related toxins may affect CMA, in this study we explored the effect of mitochondrial complex I inhibitor rotenone on CMA substrates, alpha-synuclein and MEF2D, and effectors, lamp2A and hsc70, in a human dopaminergic neuroblastoma SH-SY5Y cell line. Rotenone induced an upregulation of alpha-synuclein and MEF2D protein levels through the stimulation of theirde novosynthesis rather than through a reduction of their CMA-mediated degradation. Moreover, increased MEF2D transcription resulted in higher nuclear protein levels that exert a protective role against mitochondrial dysfunction and oxidative stress. These results were compared with those obtained after lysosome inhibition with ammonium chloride. As expected, this toxin induced the cytosolic accumulation of both alpha-synuclein and MEF2D proteins, as the result of the inhibition of their lysosome-mediated degradation, while, differently from rotenone, ammonium chloride decreased MEF2D nuclear levels through the downregulation of its transcription, thus reducing its protective function. These results highlight that rotenone affects alpha-synuclein and MEF2D protein levels through a mechanism independent from lysosomal degradation inhibition.
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Tange, Naoyuki, Fumihiko Hayakawa, Takahiko Yasuda, Hideyuki Yamamoto, Daiki Hirano, Shinobu Tsuzuki, and Hitoshi Kiyoi. "Staurosporine Induces Caspase-Dependent Proteolysis of MEF2D-Fusion Protein and Cell Death Selective to MEF2D-Fusion-Positive ALL Cells." Blood 134, Supplement_1 (November 13, 2019): 1349. http://dx.doi.org/10.1182/blood-2019-123602.
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MEF2D fusion (M-fusion) genes are newly discovered recurrent gene abnormalities that are detected in approximately 5% of acute lymphoblastic leukemia (ALL) cases. We previously found that the loss of the micro RNA target site in wild-type MEF2D gene by translocation led to strong expression of M-fusion protein in ALL cells by evasion from micro RNA and that M-fusion protein inhibited the transcriptional activity of PAX5, a B-cell differentiation regulator, in a dose-dependent manner. These findings prompted us to explore drugs that induced proteolysis of M-fusion protein as possible therapeutic agents for M-fusion-positive ALL. We developed a high-throughput screening system to find compounds that reduced protein expression level of MEF2D. The expression vector of the fusion protein of N-terminal half of MEF2D (MEF2D N) and luciferase (MEF2D N-Luc) was stably transfected to 293T cells (MEF2D N-Luc/293T). Stable transfectant of the expression vector of luciferase was also established (Luc/293T). We could easily measure protein expression level in these cells by luciferase assay. We screened 3766 compounds with known pharmaceutical activities with this system and selected staurosporine, a multi-kinase inhibitor, as a possible proteolysis-inducer of MEF2D. Staurosporine strongly reduced the luciferase value in MEF2D N-Luc/293T but not in Luc/293T (Figure 1A). Staurosporine induced proteolysis of MEF2D-HNRNPUL1 (M-H) and MEF2D-DAZAP1 (M-D) in M-fusion-positive ALL cell lines within 6 h. Proteolysis of M-fusion proteins were inhibited not by MG-132, a proteasome inhibitor, but by Z-VAD FMK, a caspase inhibitor, indicating that these proteolyses were caspase-dependent (Figure 1B). Consistent with this, Z-VAD-FMK blocked apoptosis by staurosporine in M-H positive ALL cell lines . We confirmed the cleavage of M-H by caspase 3 and caspase 7 in vitro and identified the cleavage site (Figure 1C). Furthermore, staurosporine demonstrated stronger cytotoxic effect on M-fusion-positive ALL cell lines than M-fusion-negative ones (Figure 1D). These results indicated that staurosporine induced apoptosis of M-fusion-positive ALL cells through caspase-dependent proteolysis of M-fusion protein at least in part. Luciferase-based proteolysis screening provided a novel strategy for the development of anti-cancer drugs. Figure legends Figure 1. A. Staurosporine strongly reduced the luciferase value in MEF2D N-Luc/293T but not in Luc/293T. MEF2D N-Luc/293T were treated with 3766 compounds (2uM each) for 24 h. Then luciferase assays were performed to estimate the amount of MEF2D N-Luc protein. Top 15 compounds which reduced the relative luciferase value were selected for the second screening where compounds were added to MEF2D N-Luc/293T and Luc/293T, then we estimated their effect on the expression of MEF2D N-Luc and luciferase. Results of the second screening were plotted on a scattergram, on which the relative luciferase value in Luc/293T and MEF2D N-Luc/293T were set on the Y-axis and X-axis, respectively. Relative luciferase values are relative values to those of control cells treated with vehicle (DMSO). Staurosporine and K252a, an analog of staurosporine, were selected as hit compounds which reduced MEF2D N-Luc but not luciferase. B. Staurosporine reduced the expression of M-H and M-D, which inhibited by Z-VAD FMK. M-H-positive ALL cell lines, Kasumi-7 and Kasumi-9 and a M-D-positive ALL cell line, TS-2 were treated with 1uM staurosporine, 20uM Z-VAD-FMK, or both for 6 h. Cells were lysed and subjected to immunoblotting with indicated antibodies. C. Caspase-3 and caspase-7 cleaved M-H in vitro. M-H and its mutants with aspartate substitutions at possible caspase cleavage sites were synthesized with [35S]-methionine-labeled in vitro translation and were incubated with purified caspase-3 or -7. Cleaved fragments were resolved on SDS-PAGE and visualized by autoradiography. Mutant 4 was resistant to the cleavage by both caspases. D. Staurosporine demonstrated stronger cytotoxic effect on M-fusion-positive ALL cell lines than M-fusion-negative ones. ALL cell lines were treated with staurosporine at the indicated doses for 24 h. Cell viabilities were measured using MTT assay. Figure 1 Disclosures Kiyoi: Takeda Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Eisai Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Perseus Proteomics Inc.: Research Funding.
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Hoyeck, Myriam P., Hanane Hadj-Moussa, and Kenneth B. Storey. "The role of MEF2 transcription factors in dehydration and anoxia survival inRana sylvaticaskeletal muscle." PeerJ 5 (November 9, 2017): e4014. http://dx.doi.org/10.7717/peerj.4014.
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The wood frog (Rana sylvatica) can endure freezing of up to 65% of total body water during winter. When frozen, wood frogs enter a dormant state characterized by a cessation of vital functions (i.e., no heartbeat, blood circulation, breathing, brain activity, or movement). Wood frogs utilize various behavioural and biochemical adaptations to survive extreme freezing and component anoxia and dehydration stresses, including a global suppression of metabolic functions and gene expression. The stress-responsive myocyte enhancer factor-2 (MEF2) transcription factor family regulates the selective expression of genes involved in glucose transport, protein quality control, and phosphagen homeostasis. This study examined the role of MEF2A and MEF2C proteins as well as select downstream targets (glucose transporter-4, calreticulin, and muscle and brain creatine kinase isozymes) in 40% dehydration and 24 h anoxia exposure at the transcriptional, translational, and post-translational levels using qRT-PCR, immunoblotting, and subcellular localization.Mef2a/ctranscript levels remained constant during dehydration and anoxia. Total, cytoplasmic, and nuclear MEF2A/C and phospho-MEF2A/C protein levels remained constant during dehydration, whereas a decrease in total MEF2C levels was observed during rehydration. Total and phospho-MEF2A levels remained constant during anoxia, whereas total MEF2C levels decreased during 24 h anoxia and P-MEF2C levels increased during 4 h anoxia. In contrast, cytoplasmic MEF2A levels and nuclear phospho-MEF2A/C levels were upregulated during anoxia. MEF2 downstream targets remained constant during dehydration and anoxia, with the exception ofglut4which was upregulated during anoxia. These results suggest that the upregulated MEF2 response reported in wood frogs during freezing may in part stem from their cellular responses to surviving prolonged anoxia, rather than dehydration, leading to an increase in GLUT4 expression which may have an important role during anoxia survival.
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Nagar, Saumya, Sarah M. Noveral, Dorit Trudler, Kevin M. Lopez, Scott R. McKercher, Xuemei Han, John R. Yates, et al. "MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress." Proceedings of the National Academy of Sciences 114, no. 20 (May 1, 2017): E4048—E4056. http://dx.doi.org/10.1073/pnas.1613067114.
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Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d+/− retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of light-induced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration.
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Xu, Jingyong, Yao Li, Zhe Li, Weiwei Shao, Jinghai Song, and Junmin Wei. "Acidic Tumor Microenvironment Promotes Pancreatic Cancer through miR-451a/MEF2D Axis." Journal of Oncology 2022 (January 12, 2022): 1–12. http://dx.doi.org/10.1155/2022/3966386.
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Pancreatic cancer (PC), as a highly malignant and aggressive solid tumor, is common in the digestive system. The acidic microenvironment is one of the critical markers of cancer. Nonetheless, there are few studies on how the acidic microenvironment affects the development of PC. This study focused on investigating the specific molecular mechanisms of the acidic microenvironment in PC. In our study, qRT-PCR was conducted for examining microRNA (miR)-451a and myocyte enhancer factor 2D (MEF2D) expressions in PANC-1 cells. Then, detailed functional effects of an acidic environment on miR-451a and MEF2D in PANC-1 cells were detected by CCK-8, colony formation, flow cytometry, wound healing, transwell, mitochondrial functionality measurement, JC-1 staining, DCFH-DA staining, and sphere formation assays. The relationship between miR-451a and MEF2D was confirmed by luciferase reporter analysis. Under acidic conditions, the increase of proliferation, migration, and invasion of PANC-1 cells was observed. Moreover, the mitochondrial oxidative respiration-related gene miR-451a was reduced in acidic conditions. In addition, we found that, in PANC-1 cells under an acidic environment, miR-451a overexpression enhanced oxygen consumption, mitochondrial membrane potential (MMP) loss, and ROS generation and inhibited proliferation, migration, invasion, and stemness via sponging MEF2D. In a word, our results revealed that the acidic microenvironment regulated PC progression by affecting the miR-451a/MEF2D axis, indicating a novel avenue for the future treatment of PC.
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Molkentin, J. D., B. L. Black, J. F. Martin, and E. N. Olson. "Mutational analysis of the DNA binding, dimerization, and transcriptional activation domains of MEF2C." Molecular and Cellular Biology 16, no. 6 (June 1996): 2627–36. http://dx.doi.org/10.1128/mcb.16.6.2627.
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There are four members of the myocyte enhancer factor 2 (MEF2) family of transcription factors in vertebrates, MEF2A, -B, -C, and -D, which have homology within a MADS box at their amino termini and an adjacent motif known as the MEF2 domain. These factors activate muscle gene expression by binding as homo- and heterodimers to an A/T-rich DNA sequence in the control regions of muscle-specific genes. To understand the mechanisms of muscle gene activation of MEF2 factors, we generated a series of deletion and site-directed mutants of MEF2C. These mutants demonstrated that the MADS and MEF2 domains mediate DNA binding and dimerization, whereas the carboxyl terminus is required for transcriptional activation. Amino acids that are essential for MEF2 site-dependent transcription but which do not affect DNA binding were also identified in the MEF2 domain. This type of positive-control mutant demonstrates that the transcription activation domain of MEF2C, although separate from the MEF2 domain, is dependent on this domain for transcriptional activation through the MEF2 site. MEF2 mutants that are defective for DNA binding act as dominant negative mutants and can inhibit activation of MEF2-dependent genes by wild-type MEF2C.
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Pimkin, Maxim, Juliana Xavier Ferrucio, Neekesh Vijay Dharia, Taku Harada, Andrew Kossenkov, Selma Elsarrag, Jazmin Ewers, Charles Y. Lin, Kimberly Stegmaier, and Stuart H. Orkin. "Core Transcriptional Regulatory Circuitries in AML." Blood 134, Supplement_1 (November 13, 2019): 280. http://dx.doi.org/10.1182/blood-2019-129297.
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Core transcriptional regulatory circuitries (CRCs) are tightly integrated networks of master transcription factors (TFs) that establish and maintain lineage-specific programs of gene expression. We hypothesized that divergent CRCs establish distinct subtypes of acute myeloid leukemia (AML). CRCs are defined as sets of master TFs that are marked by superenhancers (SEs) and bind to their own genes and those of the other core TFs, forming feed-forward auto-regulatory loops. We have performed large-scale H3K27ac ChIP-seq experiments to map the SE landscape in 20 AML cell lines, 3 normal hematopoietic tissues and 50 patient-derived xenograft (PDX) models of human AML. These experiments highlighted a core set of SE-marked, highly expressed TF genes shared by all the examined AML subtypes, corresponding to a putative pan-AML CRC. Importantly, a significant majority (>70%) of these transcription factors correspond to AML-specific genetic dependencies in the Project Achilles genome-scale RNAi and CRISPR-Cas9 screening efforts undertaken by colleagues at the Broad Institute, confirming the specific reliance of AML on these TFs for survival. We reasoned that CRCs can be predicted by integrating the epigenomic and functional dependency datasets. Indeed, intersecting SE-marked TF genes with preferential AML dependencies resulted in 32 candidate TFs. We have validated these TFs as AML dependencies in a low-throughput system with lentiviral delivery of Cas9 and specific gRNAs. ChiP-seq experiments with antibodies against 23 of these candidates (GATA2, PU1, IRF8, GSE1, GFI1, MEIS1, LYL1, CEBPA, MEF2D, MEF2C, IKZF1, ZEB2, FLI1, ETV6, ELF2, MAX, RUNX1, MYB, IRF2BP2, LMO2, SP1, ZMYND8, MYC) resulted in nearly 100% validation rate. They demonstrated that CRC TFs tend to co-occupy DNA and bind their own and each other's promoters and SEs, suggesting that CRC members function in higher-order chromatin complexes and establish reciprocal feed-forward regulatory loops. Analysis of TF co-binding revealed 237,636 unique binding sites, with most occupied by at least two CRC TFs. Specific combinatorial patterns of TF binding appear to be associated with promoters, enhancers and super-enhancers. Importantly, in addition to the pan-AML CRCs, highly specific dependencies restricted only to a subset of AML cell lines can be accurately predicted from examination of divergent (subtype-specific) AML CRCs, lending support to our hypothesis that context-specific vulnerabilities can be robustly inferred from a systematic study of TF circuits. Specifically, we identified MEF2D and IRF8 as TFs that are selectively marked by SEs in a subset of AML cell lines and PDXs, most notably in samples carrying an MLL rearrangement. At the same time, these genes are strong preferential dependencies in a subset of AML cell lines, most of which also carry an MLL fusion. This suggests specific roles of IRF8 and MEF2D in MLL-induced leukemogenesis. Interestingly, functional dependency scores for these two TFs show an extremely high degree of correlation, indicating tightly integrated functions. While IRF8 is a known regulator of macrophage/dendritic cell function, MEF2D has no recognized roles in hematopoiesis. We have validated MEF2D as a dependency in a low-throughput CRISPR-Cas9 drop out experiment in an MLL-rearranged cell line. At the same time, we observed no functional effect of MEF2D knock out in a human CD34+ cell colony forming assay. This confirms context-specific transcriptional addiction to MEF2D induced by an MLL fusion and suggests a potential "Achilles heel" for leukemia-specific therapy with little or no detrimental effects on normal hematopoiesis. In summary, our data allow us to draw the following conclusions: 1) Intersection of lineage-restricted gene dependencies with SE profiling permits highly specific discovery of CRCs. 2) Transcriptional control in AML is orchestrated by a large CRC of >30 essential TFs. 3) Divergent CRCs are diagnostic of cancer- and context-specific transcriptional addiction. 4) AML CRC is a highly integrated network of co-binding TFs that orchestrate both promoter- and enhancer-centric regulation. Figure Disclosures Lin: Syros Pharmaceuticals: Equity Ownership, Patents & Royalties. Stegmaier:Novartis: Research Funding; Rigel Pharmaceuticals: Consultancy. Orkin:Syros: Consultancy; Novartis: Consultancy.
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Minisini, Martina, Eros Di Giorgio, Emanuela Kerschbamer, Emiliano Dalla, Massimo Faggiani, Elisa Franforte, Franz-Josef Meyer-Almes, et al. "Transcriptomic and genomic studies classify NKL54 as a histone deacetylase inhibitor with indirect influence on MEF2-dependent transcription." Nucleic Acids Research 50, no. 5 (February 12, 2022): 2566–86. http://dx.doi.org/10.1093/nar/gkac081.
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Abstract In leiomyosarcoma class IIa HDACs (histone deacetylases) bind MEF2 and convert these transcription factors into repressors to sustain proliferation. Disruption of this complex with small molecules should antagonize cancer growth. NKL54, a PAOA (pimeloylanilide o-aminoanilide) derivative, binds a hydrophobic groove of MEF2, which is used as a docking site by class IIa HDACs. However, NKL54 could also act as HDAC inhibitor (HDACI). Therefore, it is unclear which activity is predominant. Here, we show that NKL54 and similar derivatives are unable to release MEF2 from binding to class IIa HDACs. Comparative transcriptomic analysis classifies these molecules as HDACIs strongly related to SAHA/vorinostat. Low expressed genes are upregulated by HDACIs, while abundant genes are repressed. This transcriptional resetting correlates with a reorganization of H3K27 acetylation around the transcription start site (TSS). Among the upregulated genes there are several BH3-only family members, thus explaining the induction of apoptosis. Moreover, NKL54 triggers the upregulation of MEF2 and the downregulation of class IIa HDACs. NKL54 also increases the binding of MEF2D to promoters of genes that are upregulated after treatment. In summary, although NKL54 cannot outcompete MEF2 from binding to class IIa HDACs, it supports MEF2-dependent transcription through several actions, including potentiation of chromatin binding.
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Zhu, Bangmin, and Tod Gulick. "Phosphorylation and Alternative Pre-mRNA Splicing Converge To Regulate Myocyte Enhancer Factor 2C Activity." Molecular and Cellular Biology 24, no. 18 (September 15, 2004): 8264–75. http://dx.doi.org/10.1128/mcb.24.18.8264-8275.2004.
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ABSTRACT Myocyte enhancer factor 2 (MEF2) transcription factors play pivotal roles in cardiac, muscle, and neuron gene expression. All products of MEF2 genes have a common amino-terminal DNA binding and dimerization domain, but the four vertebrate MEF2 gene transcripts are alternatively spliced among coding exons to produce splicing isoforms. In MEF2C alone, alternative splice acceptors in the last exon give forms that include or exclude a short domain that we designate γ. We show that MEF2C is expressed exclusively as γ− isoforms in heart tissue and predominantly as γ− in other adult tissues and in differentiating myocytes. MEF2C γ− isoforms are much more robust than γ+ forms in activating MEF2-responsive reporters in transfected fibroblasts despite indistinguishable expression levels, and they better synergize with MyoD in promoting myogenic conversion. One-hybrid transcription assays using Gal4-MEF2C fusions give similar distinctions between γ− and γ+ isoforms in all cell types tested, including myocytes. Cis effects of γ on MEF2C DNA binding, dimerization, protein stability, or response to CaM or p38 mitogen-activated protein kinase signaling are not apparent, and the isolated γ domain represses transcription when fused to Gal4. One phosphoserine residue is present within the γ domain according to tandem mass spectrometry, and mutation of this residue abolishes γ-mediated transrepression. A similar activity is present in the constitutive γ domain and serine phosphoacceptor of MEF2A. Our findings indicate that γ functions autonomously as a phosphoserine-dependent transrepressor to downregulate transactivation function of MEF2 factors and that alternative splicing and serine phosphorylation converge to provide complex combinatorial control of MEF2C activity.
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Borghi, Serena, Susanna Molinari, Giorgia Razzini, Flavia Parise, Renata Battini, and Stefano Ferrari. "The nuclear localization domain of the MEF2 family of transcription factors shows member-specific features and mediates the nuclear import of histone deacetylase 4." Journal of Cell Science 114, no. 24 (December 15, 2001): 4477–83. http://dx.doi.org/10.1242/jcs.114.24.4477.
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Targeting of myocyte enhancer binding factor 2 (MEF2) proteins to the nucleus depends on a C-terminal bipartite nuclear localization signal (NLS). By expression of green fluorescent protein (GFP)/MEF2 fusion proteins in transfected myoblasts, we show that MEF2C contains an additional 13 amino acids domain, located immediately upstream of the NLS, which contributes to its nuclear retention. We also show that the NLS present in MEF2 proteins is required for efficient nuclear localization of histone deacetylase 4 (HDAC4). In muscle cells, transfected HDAC4 is largely cytoplasmic or, to a lesser extent, pancellular. Co-transfection of either MEF2A or MEF2C causes HDAC4 to accumulate in the nucleus in association with MEF2. This effect strongly depends on MEF2 NLS; it also requires the specific interaction of HDAC4 with MEF2, since the isolated NLS is not sufficient for targeting HDAC4 to the nucleus and other nuclear proteins, such as NF-Y, cannot substitute MEF2. Therefore, we demonstrate that HDAC4, different from HDAC5, is mainly a cytoplasmic resident protein, requiring a trans-acting NLS for nuclear localization. The physiological implications of MEF2 carrying its own inhibitor to the nucleus are discussed.
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Suzuki, Kyogo, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, et al. "MEF2D-BCL9 Fusion Gene Is Associated With High-Risk Acute B-Cell Precursor Lymphoblastic Leukemia in Adolescents." Journal of Clinical Oncology 34, no. 28 (October 1, 2016): 3451–59. http://dx.doi.org/10.1200/jco.2016.66.5547.
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Purpose Acute lymphoblastic leukemia (ALL) makes up a significant proportion of all pediatric cancers, and relapsed ALL is a leading cause of cancer-associated deaths in children. Identification of risk factors and druggable molecular targets in ALL can lead to a better stratification of treatments and subsequent improvement in prognosis. Patients and Methods We enrolled 59 children with relapsed or primary refractory ALL who were treated in our institutions. We primarily performed RNA sequencing (RNA-seq) using patients’ leukemic cells to comprehensively detect gene fusions and analyze gene expression profiles. On the basis of results obtained by RNA-seq, we performed genetic validation, functional analysis, and in vitro drug sensitivity testing using patients’ samples and an exogenous expression model. Results We identified a total of 26 gene fusions in 22 patients by RNA-seq. Among these, 19 were nonrandom gene fusions already described in ALL, and four of the remaining seven involved identical combination of MEF2D and BCL9. All MEF2D-BCL9–positive patients had B-cell precursor immunophenotype and were characterized as being older in age, being resistant to chemotherapy, having very early relapse, and having leukemic blasts that mimic morphologically mature B-cell leukemia with markedly high expression of HDAC9. Exogenous expression of MEF2D-BCL9 in a B-cell precursor ALL cell line promoted cell growth, increased HDAC9 expression, and induced resistance to dexamethasone. Using a primary culture of leukemic blasts from a patient, we identified several molecular targeted drugs that conferred inhibitory effects in vitro. Conclusion A novel MEF2D-BCL9 fusion we identified characterizes a novel subset of pediatric ALL, predicts poor prognosis, and may be a candidate for novel molecular targeting.
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Lima, Guilherme Alves, Gabriel Forato Anhê, Gisele Giannocco, Maria Tereza Nunes, Maria Lucia Correa-Giannella, and Ubiratan Fabres Machado. "Contractile activity per se induces transcriptional activation of SLC2A4 gene in soleus muscle: involvement of MEF2D, HIF-1a, and TRα transcriptional factors." American Journal of Physiology-Endocrinology and Metabolism 296, no. 1 (January 2009): E132—E138. http://dx.doi.org/10.1152/ajpendo.90548.2008.
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Skeletal muscle is a target tissue for approaches that can improve insulin sensitivity in insulin-resistant states. In muscles, glucose uptake is performed by the GLUT-4 protein, which is encoded by the SLC2A4 gene. SLC2A4 gene expression increases in response to conditions that improve insulin sensitivity, including chronic exercise. However, since chronic exercise improves insulin sensitivity, the increased SLC2A4 gene expression could not be clearly attributed to the muscle contractile activity per se and/or to the improved insulin sensitivity. The present study was designed to investigate the role of contractile activity per se in the regulation of SLC2A4 gene expression as well as in the participation of the transcriptional factors myocyte enhancer factor 2D (MEF2D), hypoxia inducible factor 1a (HIF-1a), and thyroid hormone receptor-α (TRα). The performed in vitro protocol excluded the interference of metabolic, hormonal, and neural effects. The results showed that, in response to 10 min of electrically induced contraction of soleus muscle, an early 40% increase in GLUT-4 mRNA (30 min) occurred, with a subsequent 65% increase (120 min) in GLUT-4 protein content. EMSA and supershift assays revealed that the stimulus rapidly increased the binding activity of MEF2D, HIF-1a, and TRα into the SLC2A4 gene promoter. Furthermore, chromatin immunoprecipitation assay confirmed, in native nucleosome, that contraction induced an approximate fourfold ( P < 0.01) increase in MEF2D and HIF-1a-binding activity. In conclusion, muscle contraction per se enhances SLC2A4 gene expression and that involves MEF2D, HIF-1a, and TRα transcription factor activation. This finding reinforces the importance of physical activity to improve glycemic homeostasis independently of other additional insulin sensitizer approaches.
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Guo, Yanchun, Susanne J. Kühl, Astrid S. Pfister, Wiebke Cizelsky, Stephanie Denk, Laura Beer-Molz, and Michael Kühl. "Comparative Analysis Reveals Distinct and Overlapping Functions of Mef2c and Mef2d during Cardiogenesis in Xenopus laevis." PLoS ONE 9, no. 1 (January 28, 2014): e87294. http://dx.doi.org/10.1371/journal.pone.0087294.
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Feng, Biao, Shali Chen, Jane Chiu, Biju George, and Subrata Chakrabarti. "Regulation of cardiomyocyte hypertrophy in diabetes at the transcriptional level." American Journal of Physiology-Endocrinology and Metabolism 294, no. 6 (June 2008): E1119—E1126. http://dx.doi.org/10.1152/ajpendo.00029.2008.
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Diabetic cardiomyopathy, structurally characterized by cardiomyocyte hypertrophy and increased extracellular matrix (ECM) protein deposition, eventually leads to heart failure. We investigated the role of transcriptional coactivator p300 and its interaction with myocyte enhancer factor 2 (MEF2) in diabetes-induced cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were exposed to variable levels of glucose. Cardiomyocytes were analyzed with respect to their size. mRNA expression of p300, MEF2A, MEF2C, atrial natriuretic polypeptide (ANP), brain natriuretic polypeptide (BNP), angiotensinogen (ANG), cAMP-responsive element binding protein-binding protein (CBP), and protein analysis of MEF2 were done with or without p300 blockade. We investigated the hearts of STZ-induced diabetic rats and compared them with age- and sex-matched controls after 1 and 4 mo of followup with or without treatment with p300 blocker curcumin. The results were that cardiomyocytes, exposed to 25 mM glucose for 48 h, showed cellular hypertrophy and augmented mRNA expression of ANP, BNP, and ANG, molecular markers of cardiac hypertrophy. Glucose caused a duration-dependent increase of mRNA and protein expression in MEF2A and MEF2C and transcriptional coactivator p300. Curcumin, a p300 blocker, and p300 siRNA prevented these abnormalities. Similarly, ANP, BNP, and ANG mRNA expression was significantly higher in the hearts of diabetic rats compared with the controls, in association with increased p300, MEF2A, and MEF2C expression. Treatment with p300 blocker curcumin prevented diabetes-induced upregulation of these transcripts. We concluded that data from these studies demonstrate a novel glucose-induced epigenetic mechanism regulating gene expression and cardiomyocyte hypertrophy in diabetes.
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Al-Khalili, Lubna, Alexander V. Chibalin, Mei Yu, Bertil Sjödin, Carolina Nylén, Juleen R. Zierath, and Anna Krook. "MEF2 activation in differentiated primary human skeletal muscle cultures requires coordinated involvement of parallel pathways." American Journal of Physiology-Cell Physiology 286, no. 6 (June 2004): C1410—C1416. http://dx.doi.org/10.1152/ajpcell.00444.2003.
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The myocyte enhancer factor (MEF)2 transcription factor is important for development of differentiated skeletal muscle. We investigated the regulation of MEF2 DNA binding in differentiated primary human skeletal muscle cells and isolated rat skeletal muscle after exposure to various stimuli. MEF2 DNA binding activity in nonstimulated (basal) muscle cultures was almost undetectable. Exposure of cells for 20 min to 120 nM insulin, 0.1 and 1.0 mM hydrogen peroxide, osmotic stress (400 mM mannitol), or 1.0 mM 5-aminoimidazole-4-carboxamide-1-β- d-ribofuranoside (AICAR) led to a profound increase in MEF2 DNA binding. To study signaling pathways mediating MEF2 activity, we preincubated human skeletal muscle cell cultures or isolated rat epitrochlearis muscles with inhibitors of p38 mitogen-activated protein kinase (MAPK) (10 μM SB-203580), MEK1 (50 μM PD-98059), PKC (1 and 10 μM GF109203X), phosphatidylinositol (PI) 3-kinase (10 μM LY-294002), or AMP-activated protein kinase (AMPK; 20 μM compound C). All stimuli resulted primarily in activation of MEF2D DNA binding. Exposure of cells to osmotic or oxidative stress increased MEF2 DNA binding via pathways that were completely blocked by MAPK inhibitors and partially blocked by inhibitors of PKC, PI 3-kinase, and AMPK. In epitrochlearis muscle, MAPK inhibitors blocked contraction but not AICAR-mediated MEF2 DNA binding. Thus activation of MEF2 in skeletal muscle is regulated via parallel intracellular signaling pathways in response to insulin, cellular stress, or activation of AMPK.
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Esau, Christine, Marianne Boes, Hong-Duk Youn, Lisa Tatterson, Jun O. Liu, and Jianzhu Chen. "Deletion of Calcineurin and Myocyte Enhancer Factor 2 (MEF2) Binding Domain of Cabin1 Results in Enhanced Cytokine Gene Expression in T Cells." Journal of Experimental Medicine 194, no. 10 (November 12, 2001): 1449–59. http://dx.doi.org/10.1084/jem.194.10.1449.
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Cabin1 binds calcineurin and myocyte enhancer factor 2 (MEF2) through its COOH-terminal region. In cell lines, these interactions were shown to inhibit calcineurin activity after T cell receptor (TCR) signaling and transcriptional activation of Nur77 by MEF2. The role of these interactions under physiological conditions was investigated using a mutant mouse strain that expresses a truncated Cabin1 lacking the COOH-terminal calcineurin and MEF2 binding domains. T and B cell development and thymocyte apoptosis were normal in mutant mice. In response to anti-CD3 stimulation, however, mutant T cells expressed significantly higher levels of interleukin (IL)-2, IL-4, IL-9, IL-13, and interferon γ than wild-type T cells. The enhanced cytokine gene expression was not associated with change in nuclear factor of activated T cells (NF-AT)c or NF-ATp nuclear translocation but was preceded by the induction of a phosphorylated form of MEF2D in mutant T cells. Consistent with the enhanced cytokine expression, mutant mice had elevated levels of serum immunoglobulin (Ig)G1, IgG2b, and IgE and produced more IgG1 in response to a T cell–dependent antigen. These findings suggest that the calcineurin and MEF2 binding domain of Cabin1 is dispensable for thymocyte development and apoptosis, but is required for proper regulation of T cell cytokine expression probably through modulation of MEF2 activity.
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Tange, Naoyuki, Fumihiko Hayakawa, Takahiko Yasuda, Koya Odaira, Hideyuki Yamamoto, Daiki Hirano, Toshiyasu Sakai, Seitaro Terakura, Shinobu Tsuzuki, and Hitoshi Kiyoi. "Staurosporine and venetoclax induce the caspase-dependent proteolysis of MEF2D-fusion proteins and apoptosis in MEF2D-fusion (+) ALL cells." Biomedicine & Pharmacotherapy 128 (August 2020): 110330. http://dx.doi.org/10.1016/j.biopha.2020.110330.
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Quentmeier, Hilmar, Claudia Pommerenke, and Hans G. Drexler. "Molecular Genetics of Pre-B Acute Lymphoblastic Leukemia Sister Cell Lines during Disease Progression." Current Issues in Molecular Biology 43, no. 3 (November 30, 2021): 2147–56. http://dx.doi.org/10.3390/cimb43030149.
Full textAbstract:
For many years, immortalized tumor cell lines have been used as reliable tools to understand the function of oncogenes and tumor suppressor genes. Today, we know that tumors can comprise subclones with common and with subclone-specific genetic alterations. We sequenced DNA and RNA of sequential sister cell lines obtained from patients with pre-B acute lymphoblastic leukemia at different phases of the disease. All five pairs of cell lines carry alterations that are typical for this disease: loss of tumor suppressors (CDKN2A, CDKN2B), expression of fusion genes (ETV6-RUNX1, BCR-ABL1, MEF2D-BCL9) or of genes targeted by point mutations (KRAS A146T, NRAS G12C, PAX5 R38H). MEF2D-BCL9 and PAX R38H mutations in cell lines have hitherto been undescribed, suggesting that YCUB-4 (MEF2D-BCL9), PC-53 (PAX R38H) and their sister cell lines will be useful models to elucidate the function of these genes. All aberrations mentioned above occur in both sister cell lines, demonstrating that the sisters derive from a common ancestor. However, we also found mutations that are specific for one sister cell line only, pointing to individual subclones of the primary tumor as originating cells. Our data show that sequential sister cell lines can be used to study the clonal development of tumors and to elucidate the function of common and clone-specific mutations.