Skip to main content
SpringerLink
Log in

Cardiac Transcription Factors and Regulatory Networks

  • Chapter
Congenital Heart Diseases: The Broken Heart

Abstract

Cardiac development is a fine-tuned process governed by complex transcriptional networks, in which transcription factors (TFs) interact with other regulatory layers. In this chapter, we first introduce the core cardiac TFs including Gata, Hand, Nkx2, Mef2 and Tbx, and Srf. These factors regulate each other’s expression and also can act in a combinatorial manner on their downstream targets. Their disruption leads to various cardiac phenotypes in mice, and mutations in humans have been associated with congenital heart defects. In the second part of the chapter, we discuss different levels of regulation including cis-regulatory elements, chromatin structure, and micro-RNAs, which can interact with transcription factors, modulate their function, or are downstream targets. Finally, examples of disturbances of the cardiac regulatory network leading to congenital heart diseases in human are provided.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Buckingham M, Meilhac S, Zaffran S (2005) Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet 6:826–835

    Article  CAS  PubMed  Google Scholar 

  2. Cai C-L, Liang X, Shi Y et al (2003) Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5:877–889

    Article  CAS  PubMed  Google Scholar 

  3. Engleka KA, Manderfield LJ, Brust RD et al (2012) Islet1 derivatives in the heart are of both neural crest and second heart field origin. Circ Res 110:922–926

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Kathiriya IS, Nora EP, Bruneau BG (2015) Investigating the transcriptional control of cardiovascular development. Circ Res 116:700–714

    Article  CAS  PubMed  Google Scholar 

  5. Toenjes M, Schueler M, Hammer S et al (2008) Prediction of cardiac transcription networks based on molecular data and complex clinical phenotypes. Mol Biosyst 4:589–598

    Article  CAS  PubMed  Google Scholar 

  6. Schlesinger J, Schueler M, Grunert M et al (2011) The cardiac transcription network modulated by Gata4, Mef2a, Nkx2.5, Srf, histone modifications, and microRNAs. PLoS Genet 7, e1001313

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. He A, Kong SW, Ma Q, Pu WT (2011) Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart. Proc Natl Acad Sci U S A 108:5632–5637

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Visel A, Blow MJ, Li Z et al (2009) ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457:854–858

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Lage K, Møllgård K, Greenway S et al (2010) Dissecting spatio-temporal protein networks driving human heart development and related disorders. Mol Syst Biol 6:381

    Article  PubMed Central  PubMed  Google Scholar 

  10. Takeuchi JK, Bruneau BG (2009) Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459:708–711

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Ieda M, Fu J-D, Delgado-Olguín P et al (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142:375–386

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. McCulley DJ, Black BL (2012) Transcription factor pathways and congenital heart disease. Curr Top Dev Biol 100:253–277

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Kamohara H, Sakamoto K, Ishiko T et al (1994) Human carcinoma cell lines produce biologically active leukemia inhibitory factor (LIF). Res Commun Mol Pathol Pharmacol 85:131–140

    CAS  PubMed  Google Scholar 

  14. Takeuchi JK, Ohgi M, Koshiba-Takeuchi K et al (2003) Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis. Development 130:5953–5964

    Article  CAS  PubMed  Google Scholar 

  15. Yamagishi H, Yamagishi C, Nakagawa O et al (2001) The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation. Dev Biol 239:190–203

    Article  CAS  PubMed  Google Scholar 

  16. Vincentz JW, Barnes RM, Firulli BA et al (2008) Cooperative interaction of Nkx2.5 and Mef2c transcription factors during heart development. Dev Dyn 237:3809–3819

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Sepulveda JL, Vlahopoulos S, Iyer D et al (2002) Combinatorial expression of GATA4, Nkx2-5, and serum response factor directs early cardiac gene activity. J Biol Chem 277:25775–25782

    Article  CAS  PubMed  Google Scholar 

  18. Lyons I, Parsons LM, Hartley L et al (1995) Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev 9:1654–1666

    Article  CAS  PubMed  Google Scholar 

  19. Jay PY, Harris BS, Maguire CT et al (2004) Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system. J Clin Invest 113:1130–1137

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Clark KL, Yutzey KE, Benson DW (2006) Transcription factors and congenital heart defects. Annu Rev Physiol 68:97–121

    Article  CAS  PubMed  Google Scholar 

  21. Benson DW (2010) Genetic origins of pediatric heart disease. Pediatr Cardiol 31:422–429

    Article  PubMed  Google Scholar 

  22. Potthoff MJ, Olson EN (2007) MEF2: a central regulator of diverse developmental programs. Development 134:4131–4140

    Article  CAS  PubMed  Google Scholar 

  23. Iida K, Hidaka K, Takeuchi M et al (1999) Expression of MEF2 genes during human cardiac development. Tohoku J Exp Med 187:15–23

    Article  CAS  PubMed  Google Scholar 

  24. Amacher SL, Buskin JN, Hauschka SD (1993) Multiple regulatory elements contribute differentially to muscle creatine kinase enhancer activity in skeletal and cardiac muscle. Mol Cell Biol 13:2753–2764

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Lange M, Kaynak B, Forster UB et al (2008) Regulation of muscle development by DPF3, a novel histone acetylation and methylation reader of the BAF chromatin remodeling complex. Genes Dev 22:2370–2384

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Ghosh TK, Song FF, Packham EA et al (2009) Physical interaction between TBX5 and MEF2C is required for early heart development. Mol Cell Biol 29:2205–2218

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Olson EN (2006) Gene regulatory networks in the evolution and development of the heart. Science 313:1922–1927

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Karamboulas C, Dakubo GD, Liu J et al (2006) Disruption of MEF2 activity in cardiomyoblasts inhibits cardiomyogenesis. J Cell Sci 119:4315–4321

    Article  CAS  PubMed  Google Scholar 

  29. Lu J, McKinsey TA, Zhang CL, Olson EN (2000) Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases. Mol Cell 6:233–244

    Article  CAS  PubMed  Google Scholar 

  30. Chen J-F, Mandel EM, Thomson JM et al (2006) The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 38:228–233

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Naya FJ, Black BL, Wu H et al (2002) Mitochondrial deficiency and cardiac sudden death in mice lacking the MEF2A transcription factor. Nat Med 8:1303–1309

    Article  CAS  PubMed  Google Scholar 

  32. Wang L, Fan C, Topol SE et al (2003) Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science 302:1578–1581

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Lin Q, Schwarz J, Bucana C, Olson EN (1997) Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science 276:1404–1407

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Verzi MP, McCulley DJ, De Val S et al (2005) The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary/anterior heart field. Dev Biol 287:134–145

    Article  CAS  PubMed  Google Scholar 

  35. Nemer M (2008) Genetic insights into normal and abnormal heart development. Cardiovasc Pathol 17:48–54

    Article  CAS  PubMed  Google Scholar 

  36. Plageman TF, Yutzey KE (2005) T-box genes and heart development: putting the “T” in heart. Dev Dyn 232:11–20

    Article  CAS  PubMed  Google Scholar 

  37. Mesbah K, Rana MS, Francou A et al (2012) Identification of a Tbx1/Tbx2/Tbx3 genetic pathway governing pharyngeal and arterial pole morphogenesis. Hum Mol Genet 21:1217–1229

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Hatcher CJ, Basson CT (2009) Specification of the cardiac conduction system by transcription factors. Circ Res 105:620–630

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Bruneau BG, Nemer G, Schmitt JP et al (2001) A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell 106:709–721

    Article  CAS  PubMed  Google Scholar 

  40. Takeuchi JK, Mileikovskaia M, Koshiba-Takeuchi K et al (2005) Tbx20 dose-dependently regulates transcription factor networks required for mouse heart and motoneuron development. Development 132:2463–2474

    Article  CAS  PubMed  Google Scholar 

  41. Maitra M, Schluterman MK, Nichols HA et al (2009) Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development. Dev Biol 326:368–377

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Basson CT, Bachinsky DR, Lin RC et al (1997) Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 15:30–35

    Article  CAS  PubMed  Google Scholar 

  43. Smemo S, Campos LC, Moskowitz IP et al (2012) Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease. Hum Mol Genet 21:3255–3263

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Merscher S, Funke B, Epstein JA et al (2001) TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104:619–629

    Article  CAS  PubMed  Google Scholar 

  45. Meneghini V, Odent S, Platonova N et al (2006) Novel TBX3 mutation data in families with ulnar-mammary syndrome indicate a genotype-phenotype relationship: mutations that do not disrupt the T-domain are associated with less severe limb defects. Eur J Med Genet 49:151–158

    Article  PubMed  Google Scholar 

  46. Kirk EP, Sunde M, Costa MW et al (2007) Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy. Am J Hum Genet 81:280–291

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Ma L, Li J, Liu Y et al (2013) Novel and functional variants within the TBX18 gene promoter in ventricular septal defects. Mol Cell Biochem 382:121–126

    Article  CAS  PubMed  Google Scholar 

  48. Peterkin T, Gibson A, Loose M, Patient R (2005) The roles of GATA-4, -5 and -6 in vertebrate heart development. Semin Cell Dev Biol 16:83–94

    Article  CAS  PubMed  Google Scholar 

  49. Pikkarainen S, Tokola H, Kerkelä R, Ruskoaho H (2004) GATA transcription factors in the developing and adult heart. Cardiovasc Res 63:196–207

    Article  CAS  PubMed  Google Scholar 

  50. Dai Y-S, Cserjesi P, Markham BE, Molkentin JD (2002) The transcription factors GATA4 and dHAND physically interact to synergistically activate cardiac gene expression through a p300-dependent mechanism. J Biol Chem 277:24390–24398

    Article  CAS  PubMed  Google Scholar 

  51. Lee Y, Shioi T, Kasahara H et al (1998) The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression. Mol Cell Biol 18:3120–3129

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Morin S, Charron F, Robitaille L, Nemer M (2000) GATA-dependent recruitment of MEF2 proteins to target promoters. EMBO J 19:2046–2055

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Belaguli NS, Sepulveda JL, Nigam V et al (2000) Cardiac tissue enriched factors serum response factor and GATA-4 are mutual coregulators. Mol Cell Biol 20:7550–7558

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Garg V, Kathiriya IS, Barnes R et al (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443–447

    Article  CAS  PubMed  Google Scholar 

  55. Moorman AFM, Christoffels VM (2003) Cardiac chamber formation: development, genes, and evolution. Physiol Rev 83:1223–1267

    Article  CAS  PubMed  Google Scholar 

  56. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705

    Article  CAS  PubMed  Google Scholar 

  57. Davis FJ, Gupta M, Camoretti-Mercado B et al (2003) Calcium/calmodulin-dependent protein kinase activates serum response factor transcription activity by its dissociation from histone deacetylase, HDAC4. Implications in cardiac muscle gene regulation during hypertrophy. J Biol Chem 278:20047–20058

    Article  CAS  PubMed  Google Scholar 

  58. He A, Gu F, Hu Y et al (2014) Dynamic GATA4 enhancers shape the chromatin landscape central to heart development and disease. Nat Commun 5:4907

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Molkentin JD, Lin Q, Duncan SA, Olson EN (1997) Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev 11:1061–1072

    Article  CAS  PubMed  Google Scholar 

  60. Pu WT, Ishiwata T, Juraszek AL et al (2004) GATA4 is a dosage-sensitive regulator of cardiac morphogenesis. Dev Biol 275:235–244

    Article  CAS  PubMed  Google Scholar 

  61. Srivastava D, Thomas T, Lin Q et al (1997) Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND. Nat Genet 16:154–160

    Article  CAS  PubMed  Google Scholar 

  62. Tsuchihashi T, Maeda J, Shin CH et al (2011) Hand2 function in second heart field progenitors is essential for cardiogenesis. Dev Biol 351:62–69

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Riley PR, Gertsenstein M, Dawson K, Cross JC (2000) Early exclusion of hand1-deficient cells from distinct regions of the left ventricular myocardium in chimeric mouse embryos. Dev Biol 227:156–168

    Article  CAS  PubMed  Google Scholar 

  64. McFadden DG, Barbosa AC, Richardson JA et al (2005) The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner. Development 132:189–201

    Article  CAS  PubMed  Google Scholar 

  65. Dodou E, Verzi MP, Anderson JP et al (2004) Mef2c is a direct transcriptional target of ISL1 and GATA factors in the anterior heart field during mouse embryonic development. Development 131:3931–3942

    Article  CAS  PubMed  Google Scholar 

  66. Laugwitz K-L, Moretti A, Caron L et al (2008) Islet1 cardiovascular progenitors: a single source for heart lineages? Development 135:193–205

    Article  CAS  PubMed  Google Scholar 

  67. Stevens KN, Hakonarson H, Kim CE et al (2009) Common variation in ISL1 confers genetic susceptibility for human congenital heart disease. PLoS One 5:e10855

    Article  Google Scholar 

  68. Miano JM, Long X, Fujiwara K (2007) Serum response factor: master regulator of the actin cytoskeleton and contractile apparatus. Am J Physiol Cell Physiol 292:C70–C81

    Article  CAS  PubMed  Google Scholar 

  69. Parlakian A, Tuil D, Hamard G et al (2004) Targeted inactivation of serum response factor in the developing heart results in myocardial defects and embryonic lethality. Mol Cell Biol 24:5281–5289

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Belaguli NS, Schildmeyer LA, Schwartz RJ (1997) Organization and myogenic restricted expression of the murine serum response factor gene. A role for autoregulation. J Biol Chem 272:18222–18231

    Article  CAS  PubMed  Google Scholar 

  71. Wang D, Chang PS, Wang Z et al (2001) Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell 105:851–862

    Article  CAS  PubMed  Google Scholar 

  72. Cao D, Wang Z, Zhang C-L et al (2005) Modulation of smooth muscle gene expression by association of histone acetyltransferases and deacetylases with myocardin. Mol Cell Biol 25:364–376

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Schueler M, Zhang Q, Schlesinger J et al (2012) Dynamics of Srf, p300 and histone modifications during cardiac maturation in mouse. Mol Biosyst 8:495–503

    Article  CAS  PubMed  Google Scholar 

  74. Kook H, Lepore JJ, Gitler AD et al (2003) Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. J Clin Invest 112:863–871

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Cordes KR, Sheehy NT, White MP et al (2009) miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature 460:705–710

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Chen L, Fulcoli FG, Tang S, Baldini A (2009) Tbx1 regulates proliferation and differentiation of multipotent heart progenitors. Circ Res 105:842–851

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. ENCODE Project Consortium, Birney E, Stamatoyannopoulos JA et al (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447:799–816

    Article  Google Scholar 

  78. Ernst J, Kellis M (2013) Interplay between chromatin state, regulator binding, and regulatory motifs in six human cell types. Genome Res 23:1142–1154

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Narlikar L, Sakabe NJ, Blanski AA et al (2010) Genome-wide discovery of human heart enhancers. Genome Res 20:381–392

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Guo Z, Maki M, Ding R et al (2014) Genome-wide survey of tissue-specific microRNA and transcription factor regulatory networks in 12 tissues. Sci Rep 4:5150

    PubMed  Google Scholar 

  81. Kaynak B, von Heydebreck A, Mebus S et al (2003) Genome-wide array analysis of normal and malformed human hearts. Circulation 107:2467–2474

    Article  PubMed  Google Scholar 

  82. Zaidi S, Choi M, Wakimoto H et al (2013) De novo mutations in histone-modifying genes in congenital heart disease. Nature 498:220–223

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Grunert M, Dorn C, Schueler M et al (2014) Rare and private variations in neural crest, apoptosis and sacromere genes define the polygenic background of isolated Tetralogy of Fallot. Hum Mol Genet 23:3115–3128

    Article  CAS  PubMed  Google Scholar 

  84. Greenway SC, Pereira AC, Lin JC et al (2009) De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet 41:931–935

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Theodoris CV, Li M, White MP et al (2015) Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency. Cell 160:1072–1086

    Article  CAS  PubMed  Google Scholar 

  86. Sotoodehnia N, Isaacs A, de Bakker PIW et al (2010) Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nat Genet 42:1068–1076

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. van den Boogaard M, Wong LYE, Tessadori F et al (2012) Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer. J Clin Invest 122:2519–2530

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the European Community’s Seventh Framework Programme contract (“CardioNeT”) grant 289600 to SRS and the German Research Foundation (Heisenberg professorship and grant 574157 to SRS). This work was also supported by the Berlin Institute of Health (BIH-CRG2-ConDi to SRS).

Author information

Authors and Affiliations

  1. Cardiovascular Genetics, Charité – Universitätsmedizin Berlin, Berlin, Germany

    Marcel Grunert, Cornelia Dorn & Silke Rickert-Sperling

Authors
  1. Marcel Grunert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cornelia Dorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silke Rickert-Sperling
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Silke Rickert-Sperling .

Editor information

Editors and Affiliations

  1. Cardiovascular Genetics, Charité - Universitätsmedizin Berlin , Berlin, Germany

    Silke Rickert-Sperling

  2. Developmental Biology, Inst. of Marseilles, Aix-Marseille Univ. , Marseille, France

    Robert G. Kelly

  3. Dpt. of Pediatrics Div.of Pediatric Card, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

    David J. Driscoll

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer-Verlag Wien

About this chapter

Cite this chapter

Grunert, M., Dorn, C., Rickert-Sperling, S. (2016). Cardiac Transcription Factors and Regulatory Networks. In: Rickert-Sperling, S., Kelly, R., Driscoll, D. (eds) Congenital Heart Diseases: The Broken Heart. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1883-2_12

Download citation

Publish with us

Policies and ethics

Search

Navigation