Skip to main content
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1993 Apr;13(4):2564–2577. doi: 10.1128/mcb.13.4.2564

hMEF2C gene encodes skeletal muscle- and brain-specific transcription factors.

J C McDermott 1, M C Cardoso 1, Y T Yu 1, V Andres 1, D Leifer 1, D Krainc 1, S A Lipton 1, B Nadal-Ginard 1
PMCID: PMC359588  PMID: 8455629

Abstract

The myocyte enhancer-binding factor 2 (MEF2) site is an essential element of many muscle-specific enhancers and promoters that binds nuclear proteins from muscle and brain. Recently, we have cloned a family of MEF2 transcription factors produced by two genes that, at the mRNA level, are broadly expressed and produce tissue-specific isoforms by posttranscriptional processes (Y.-T. Yu, R. E. Breitbart, L. B. Smoot, Y. Lee, V. Mahdavi, and B. Nadal-Ginard, Genes Dev. 6:1783-1798, 1992). Here, we report the isolation and functional characterization of cDNA clones encoding four MEF2 factors derived from a separate gene that we have named hMEF2C. In contrast to those of the previously reported genes, the transcripts of the hMEF2C gene are restricted to skeletal muscle and brain. One of the alternate exons is exclusively present in brain transcripts. The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors. The hMEF2C gene is induced late during myogenic differentiation, and its expression is limited to a subset of cortical neurons. The potential targets for this transcription factor in a subset of neurons are not known at this time. The strict tissue-specific pattern of expression of hMEF2C in comparison with the more ubiquitous expression of other MEF2 genes suggests a different mode of regulation and a potentially important role of hMEF2C factors in myogenesis and neurogenesis.

Full text

PDF
2564

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bader D., Masaki T., Fischman D. A. Immunochemical analysis of myosin heavy chain during avian myogenesis in vivo and in vitro. J Cell Biol. 1982 Dec;95(3):763–770. doi: 10.1083/jcb.95.3.763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bouvagnet P. F., Strehler E. E., White G. E., Strehler-Page M. A., Nadal-Ginard B., Mahdavi V. Multiple positive and negative 5' regulatory elements control the cell-type-specific expression of the embryonic skeletal myosin heavy-chain gene. Mol Cell Biol. 1987 Dec;7(12):4377–4389. doi: 10.1128/mcb.7.12.4377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boxer L. M., Prywes R., Roeder R. G., Kedes L. The sarcomeric actin CArG-binding factor is indistinguishable from the c-fos serum response factor. Mol Cell Biol. 1989 Feb;9(2):515–522. doi: 10.1128/mcb.9.2.515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Braun T., Bober E., Buschhausen-Denker G., Kohtz S., Grzeschik K. H., Arnold H. H., Kotz S. Differential expression of myogenic determination genes in muscle cells: possible autoactivation by the Myf gene products. EMBO J. 1989 Dec 1;8(12):3617–3625. doi: 10.1002/j.1460-2075.1989.tb08535.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Braun T., Tannich E., Buschhausen-Denker G., Arnold H. H. Promoter upstream elements of the chicken cardiac myosin light-chain 2-A gene interact with trans-acting regulatory factors for muscle-specific transcription. Mol Cell Biol. 1989 Jun;9(6):2513–2525. doi: 10.1128/mcb.9.6.2513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Breitbart R. E., Andreadis A., Nadal-Ginard B. Alternative splicing: a ubiquitous mechanism for the generation of multiple protein isoforms from single genes. Annu Rev Biochem. 1987;56:467–495. doi: 10.1146/annurev.bi.56.070187.002343. [DOI] [PubMed] [Google Scholar]
  7. Buskin J. N., Hauschka S. D. Identification of a myocyte nuclear factor that binds to the muscle-specific enhancer of the mouse muscle creatine kinase gene. Mol Cell Biol. 1989 Jun;9(6):2627–2640. doi: 10.1128/mcb.9.6.2627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  9. Coen E. S., Meyerowitz E. M. The war of the whorls: genetic interactions controlling flower development. Nature. 1991 Sep 5;353(6339):31–37. doi: 10.1038/353031a0. [DOI] [PubMed] [Google Scholar]
  10. Courey A. J., Tjian R. Analysis of Sp1 in vivo reveals multiple transcriptional domains, including a novel glutamine-rich activation motif. Cell. 1988 Dec 2;55(5):887–898. doi: 10.1016/0092-8674(88)90144-4. [DOI] [PubMed] [Google Scholar]
  11. Cserjesi P., Olson E. N. Myogenin induces the myocyte-specific enhancer binding factor MEF-2 independently of other muscle-specific gene products. Mol Cell Biol. 1991 Oct;11(10):4854–4862. doi: 10.1128/mcb.11.10.4854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dalton S., Treisman R. Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element. Cell. 1992 Feb 7;68(3):597–612. doi: 10.1016/0092-8674(92)90194-h. [DOI] [PubMed] [Google Scholar]
  13. Davis R. L., Weintraub H., Lassar A. B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987 Dec 24;51(6):987–1000. doi: 10.1016/0092-8674(87)90585-x. [DOI] [PubMed] [Google Scholar]
  14. Devereux J., Haeberli P., Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. doi: 10.1093/nar/12.1part1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Edmondson D. G., Cheng T. C., Cserjesi P., Chakraborty T., Olson E. N. Analysis of the myogenin promoter reveals an indirect pathway for positive autoregulation mediated by the muscle-specific enhancer factor MEF-2. Mol Cell Biol. 1992 Sep;12(9):3665–3677. doi: 10.1128/mcb.12.9.3665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Foulkes N. S., Sassone-Corsi P. More is better: activators and repressors from the same gene. Cell. 1992 Feb 7;68(3):411–414. doi: 10.1016/0092-8674(92)90178-f. [DOI] [PubMed] [Google Scholar]
  17. Garnier J., Osguthorpe D. J., Robson B. Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J Mol Biol. 1978 Mar 25;120(1):97–120. doi: 10.1016/0022-2836(78)90297-8. [DOI] [PubMed] [Google Scholar]
  18. Gilgenkrantz H., Hugnot J. P., Lambert M., Chafey P., Kaplan J. C., Kahn A. Positive and negative regulatory DNA elements including a CCArGG box are involved in the cell type-specific expression of the human muscle dystrophin gene. J Biol Chem. 1992 May 25;267(15):10823–10830. [PubMed] [Google Scholar]
  19. Gossett L. A., Kelvin D. J., Sternberg E. A., Olson E. N. A new myocyte-specific enhancer-binding factor that recognizes a conserved element associated with multiple muscle-specific genes. Mol Cell Biol. 1989 Nov;9(11):5022–5033. doi: 10.1128/mcb.9.11.5022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Grueneberg D. A., Natesan S., Alexandre C., Gilman M. Z. Human and Drosophila homeodomain proteins that enhance the DNA-binding activity of serum response factor. Science. 1992 Aug 21;257(5073):1089–1095. doi: 10.1126/science.257.5073.1089. [DOI] [PubMed] [Google Scholar]
  21. Horlick R. A., Hobson G. M., Patterson J. H., Mitchell M. T., Benfield P. A. Brain and muscle creatine kinase genes contain common TA-rich recognition protein-binding regulatory elements. Mol Cell Biol. 1990 Sep;10(9):4826–4836. doi: 10.1128/mcb.10.9.4826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Iannello R. C., Mar J. H., Ordahl C. P. Characterization of a promoter element required for transcription in myocardial cells. J Biol Chem. 1991 Feb 15;266(5):3309–3316. [PubMed] [Google Scholar]
  23. Jack T., Brockman L. L., Meyerowitz E. M. The homeotic gene APETALA3 of Arabidopsis thaliana encodes a MADS box and is expressed in petals and stamens. Cell. 1992 Feb 21;68(4):683–697. doi: 10.1016/0092-8674(92)90144-2. [DOI] [PubMed] [Google Scholar]
  24. Kaufman R. J., Davies M. V., Pathak V. K., Hershey J. W. The phosphorylation state of eucaryotic initiation factor 2 alters translational efficiency of specific mRNAs. Mol Cell Biol. 1989 Mar;9(3):946–958. doi: 10.1128/mcb.9.3.946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kinloch R. A., Mortillo S., Wassarman P. M. Transgenic mouse eggs with functional hamster sperm receptors in their zona pellucida. Development. 1992 Aug;115(4):937–946. doi: 10.1242/dev.115.4.937. [DOI] [PubMed] [Google Scholar]
  26. Kozak M. An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 1987 Oct 26;15(20):8125–8148. doi: 10.1093/nar/15.20.8125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lassar A. B., Davis R. L., Wright W. E., Kadesch T., Murre C., Voronova A., Baltimore D., Weintraub H. Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12/E47-like proteins in vivo. Cell. 1991 Jul 26;66(2):305–315. doi: 10.1016/0092-8674(91)90620-e. [DOI] [PubMed] [Google Scholar]
  28. Ma H., Yanofsky M. F., Meyerowitz E. M. AGL1-AGL6, an Arabidopsis gene family with similarity to floral homeotic and transcription factor genes. Genes Dev. 1991 Mar;5(3):484–495. doi: 10.1101/gad.5.3.484. [DOI] [PubMed] [Google Scholar]
  29. Mar J. H., Ordahl C. P. M-CAT binding factor, a novel trans-acting factor governing muscle-specific transcription. Mol Cell Biol. 1990 Aug;10(8):4271–4283. doi: 10.1128/mcb.10.8.4271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. McKnight S. L., Kingsbury R. Transcriptional control signals of a eukaryotic protein-coding gene. Science. 1982 Jul 23;217(4557):316–324. doi: 10.1126/science.6283634. [DOI] [PubMed] [Google Scholar]
  31. Mermod N., O'Neill E. A., Kelly T. J., Tjian R. The proline-rich transcriptional activator of CTF/NF-I is distinct from the replication and DNA binding domain. Cell. 1989 Aug 25;58(4):741–753. doi: 10.1016/0092-8674(89)90108-6. [DOI] [PubMed] [Google Scholar]
  32. Moreau P., Hen R., Wasylyk B., Everett R., Gaub M. P., Chambon P. The SV40 72 base repair repeat has a striking effect on gene expression both in SV40 and other chimeric recombinants. Nucleic Acids Res. 1981 Nov 25;9(22):6047–6068. doi: 10.1093/nar/9.22.6047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Muscat G. E., Perry S., Prentice H., Kedes L. The human skeletal alpha-actin gene is regulated by a muscle-specific enhancer that binds three nuclear factors. Gene Expr. 1992;2(2):111–126. [PMC free article] [PubMed] [Google Scholar]
  34. Nakatsuji Y., Hidaka K., Tsujino S., Yamamoto Y., Mukai T., Yanagihara T., Kishimoto T., Sakoda S. A single MEF-2 site is a major positive regulatory element required for transcription of the muscle-specific subunit of the human phosphoglycerate mutase gene in skeletal and cardiac muscle cells. Mol Cell Biol. 1992 Oct;12(10):4384–4390. doi: 10.1128/mcb.12.10.4384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Norman C., Runswick M., Pollock R., Treisman R. Isolation and properties of cDNA clones encoding SRF, a transcription factor that binds to the c-fos serum response element. Cell. 1988 Dec 23;55(6):989–1003. doi: 10.1016/0092-8674(88)90244-9. [DOI] [PubMed] [Google Scholar]
  36. Olson E. N. MyoD family: a paradigm for development? Genes Dev. 1990 Sep;4(9):1454–1461. doi: 10.1101/gad.4.9.1454. [DOI] [PubMed] [Google Scholar]
  37. Parvin J. D., Timmers H. T., Sharp P. A. Promoter specificity of basal transcription factors. Cell. 1992 Mar 20;68(6):1135–1144. doi: 10.1016/0092-8674(92)90084-p. [DOI] [PubMed] [Google Scholar]
  38. Passmore S., Maine G. T., Elble R., Christ C., Tye B. K. Saccharomyces cerevisiae protein involved in plasmid maintenance is necessary for mating of MAT alpha cells. J Mol Biol. 1988 Dec 5;204(3):593–606. doi: 10.1016/0022-2836(88)90358-0. [DOI] [PubMed] [Google Scholar]
  39. Pnueli L., Abu-Abeid M., Zamir D., Nacken W., Schwarz-Sommer Z., Lifschitz E. The MADS box gene family in tomato: temporal expression during floral development, conserved secondary structures and homology with homeotic genes from Antirrhinum and Arabidopsis. Plant J. 1991 Sep;1(2):255–266. [PubMed] [Google Scholar]
  40. Pollock R., Treisman R. Human SRF-related proteins: DNA-binding properties and potential regulatory targets. Genes Dev. 1991 Dec;5(12A):2327–2341. doi: 10.1101/gad.5.12a.2327. [DOI] [PubMed] [Google Scholar]
  41. Roman C., Cohn L., Calame K. A dominant negative form of transcription activator mTFE3 created by differential splicing. Science. 1991 Oct 4;254(5028):94–97. doi: 10.1126/science.1840705. [DOI] [PubMed] [Google Scholar]
  42. Sassoon D., Lyons G., Wright W. E., Lin V., Lassar A., Weintraub H., Buckingham M. Expression of two myogenic regulatory factors myogenin and MyoD1 during mouse embryogenesis. Nature. 1989 Sep 28;341(6240):303–307. doi: 10.1038/341303a0. [DOI] [PubMed] [Google Scholar]
  43. Schwarz-Sommer Z., Huijser P., Nacken W., Saedler H., Sommer H. Genetic Control of Flower Development by Homeotic Genes in Antirrhinum majus. Science. 1990 Nov 16;250(4983):931–936. doi: 10.1126/science.250.4983.931. [DOI] [PubMed] [Google Scholar]
  44. Shaw P. E., Schröter H., Nordheim A. The ability of a ternary complex to form over the serum response element correlates with serum inducibility of the human c-fos promoter. Cell. 1989 Feb 24;56(4):563–572. doi: 10.1016/0092-8674(89)90579-5. [DOI] [PubMed] [Google Scholar]
  45. Smith C. W., Patton J. G., Nadal-Ginard B. Alternative splicing in the control of gene expression. Annu Rev Genet. 1989;23:527–577. doi: 10.1146/annurev.ge.23.120189.002523. [DOI] [PubMed] [Google Scholar]
  46. Smith D. L., Johnson A. D. A molecular mechanism for combinatorial control in yeast: MCM1 protein sets the spacing and orientation of the homeodomains of an alpha 2 dimer. Cell. 1992 Jan 10;68(1):133–142. doi: 10.1016/0092-8674(92)90212-u. [DOI] [PubMed] [Google Scholar]
  47. Thompson W. R., Nadal-Ginard B., Mahdavi V. A MyoD1-independent muscle-specific enhancer controls the expression of the beta-myosin heavy chain gene in skeletal and cardiac muscle cells. J Biol Chem. 1991 Nov 25;266(33):22678–22688. [PubMed] [Google Scholar]
  48. Weintraub H., Davis R., Tapscott S., Thayer M., Krause M., Benezra R., Blackwell T. K., Turner D., Rupp R., Hollenberg S. The myoD gene family: nodal point during specification of the muscle cell lineage. Science. 1991 Feb 15;251(4995):761–766. doi: 10.1126/science.1846704. [DOI] [PubMed] [Google Scholar]
  49. Yanofsky M. F., Ma H., Bowman J. L., Drews G. N., Feldmann K. A., Meyerowitz E. M. The protein encoded by the Arabidopsis homeotic gene agamous resembles transcription factors. Nature. 1990 Jul 5;346(6279):35–39. doi: 10.1038/346035a0. [DOI] [PubMed] [Google Scholar]
  50. Yu Y. T., Breitbart R. E., Smoot L. B., Lee Y., Mahdavi V., Nadal-Ginard B. Human myocyte-specific enhancer factor 2 comprises a group of tissue-restricted MADS box transcription factors. Genes Dev. 1992 Sep;6(9):1783–1798. doi: 10.1101/gad.6.9.1783. [DOI] [PubMed] [Google Scholar]
  51. Zhu H., Garcia A. V., Ross R. S., Evans S. M., Chien K. R. A conserved 28-base-pair element (HF-1) in the rat cardiac myosin light-chain-2 gene confers cardiac-specific and alpha-adrenergic-inducible expression in cultured neonatal rat myocardial cells. Mol Cell Biol. 1991 Apr;11(4):2273–2281. doi: 10.1128/mcb.11.4.2273. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES