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NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets

Bouveret, Romaric, Waardenberg, Ashley J, Schonrock, Nicole, Ramialison, Mirana, Doan, Tram, de Jong, Danielle, Bondue, Antoine, Kaur, Gurpreet, Mohamed, Stephanie, Fonoudi, Hananeh, Chen, Chiann-mun, Wouters, Merridee A, Bhattacharya, Shoumo, Plachta, Nicolas, Dunwoodie, Sally L, Chapman, Gavin, Blanpain, Cédric, Harvey, Richard P·2015·eLife
DOI 10.7554/elife.06942PMC PMC4548209
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Abstract

We take a functional genomics approach to congenital heart disease mechanism. We used DamID to establish a robust set of target genes for NKX2-5 wild type and disease associated NKX2-5 mutations to model loss-of-function in gene regulatory networks. NKX2-5 mutants, including those with a crippled homeodomain, bound hundreds of targets including NKX2-5 wild type targets and a unique set of "off-targets", and retained partial functionality. NKXΔHD, which lacks the homeodomain completely, could heterodimerize with NKX2-5 wild type and its cofactors, including E26 transformation-specific (ETS) family members, through a tyrosine-rich homophilic interaction domain (YRD). Off-targets of NKX2-5 mutants, but not those of an NKX2-5 YRD mutant, showed overrepresentation of ETS binding sites and were occupied by ETS proteins, as determined by DamID. Analysis of kernel transcription factor and ETS targets show that ETS proteins are highly embedded within the cardiac gene regulatory network. Our study reveals binding and activities of NKX2-5 mutations on WT target and off-targets, guided by interactions with their normal cardiac and general cofactors, and suggest a novel type of gain-of-function in congenital heart disease.

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  • A strong cardiac cis-regulatory signature was observed in Category I with enrichment of binding sites of known master regulators of cardiac development, such as Nkx2-5 and Tbx5.

    “A strong cardiac cis-regulatory signature was observed in Category I with the enrichment of binding sites of known master regulators of cardiac development, such as Nkx2-5 and Tbx5, which when mutated account for the genetic causes of CHD (Fig. 2C, i) [2, 25].”

    From A cis-regulatory-directed pipeline for the identification of genes involved in cardiac development and disease (2021) · cites this paper as [25]

    The Results section on NKX2-5 mutant targets reports enrichment of NKX2-5 binding motifs in the paper’s A- and B-sets, and the Figure 1 caption identifies NKX2-5 mutations associated with congenital heart disease. The cited paper does not report the citing document’s Category I signature or enrichment of Tbx5 binding sites; its analyses concern different target sets. (LLM, conf=0.84)

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Research works printed but not linked: 87

  1. Bachurski, 2003, Nuclear factor I/thyroid transcription factor 1 interactions modulate surfactant protein C transcription, Molecular and Cellular Biology, 23, 9014, 10.1128/MCB.23.24.9014-9024.2003 · DOI
  2. Badis, 2009, Diversity and complexity in DNA recognition by transcription factors, Science, 324, 1720, 10.1126/science.1162327 · DOI
  3. Benson, 1999, Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways, The Journal of Clinical Investigation, 104, 1567, 10.1172/JCI8154 · DOI · Paper page
  4. Berger, 2008, Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences, Cell, 133, 1266, 10.1016/j.cell.2008.05.024 · DOI · Paper page
  5. Bondue, 2008, Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification, Cell Stem Cell, 3, 69, 10.1016/j.stem.2008.06.009 · DOI
  6. Bondue, 2011, Defining the earliest step of cardiovascular progenitor specification during embryonic stem cell differentiation, The Journal of Cell Biology, 192, 751, 10.1083/jcb.201007063 · DOI
  7. Boros, 2009b, Overlapping promoter targeting by Elk-1 and other divergent ETS-domain transcription factor family members, Nucleic Acids Research, 37, 7368, 10.1093/nar/gkp804 · DOI · Paper page
  8. Bouveret, 2015, NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets, 10.7554/eLife.06942
  9. Bryne, 2008, JASPAR, the open access database of transcription factor-binding profiles: new content and tools in the 2008 update, Nucleic Acids Research, 36, D102, 10.1093/nar/gkm955 · DOI
  10. Chapman, 2011, Notch inhibition by the ligand DELTA-LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis, Human Molecular Genetics, 20, 905, 10.1093/hmg/ddq529 · DOI
  11. Chen, 1995, Identification of novel DNA binding targets and regulatory domains of a murine tinman homeodomain factor, nkx-2.5, The Journal of Biological Chemistry, 270, 15628, 10.1074/jbc.270.26.15628 · DOI · Paper page
  12. Chen, 1997, Competition between negative acting YY1 versus positive acting serum response factor and tinman homologue Nkx-2.5 regulates cardiac alpha-actin promoter activity, Molecular Endocrinology, 11, 812
  13. Chen, 2005, Structural and functional analysis of domains mediating interaction between NKX-3.1 and PDEF, Journal of Cellular Biochemistry, 94, 168, 10.1002/jcb.20297 · DOI
  14. Chen, 2007, Characterization of spectral FRET imaging microscopy for monitoring nuclear protein interactions, Journal of Microscopy, 228, 139, 10.1111/j.1365-2818.2007.01838.x · DOI
  15. Claycomb, 1998, HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte, Proceedings of the National Academy of Sciences of USA, 95, 2979, 10.1073/pnas.95.6.2979 · DOI · Paper page
  16. Costa, 2011, Complex SUMO-1 regulation of cardiac transcription factor Nkx2-5, PLOS ONE, 6, e24812, 10.1371/journal.pone.0024812 · DOI
  17. Davidson, 2006, FGF signaling delineates the cardiac progenitor field in the simple chordate, Ciona intestinalis, Genes & Development, 20, 2728, 10.1101/gad.1467706 · DOI
  18. Ding, 2006, p204 protein overcomes the inhibition of the differentiation of P19 murine embryonal carcinoma cells to beating cardiac myocytes by Id proteins, The Journal of Biological Chemistry, 281, 14893, 10.1074/jbc.M511748200 · DOI
  19. Dull, 1998, A third-generation lentivirus vector with a conditional packaging system, Journal of Virology, 72, 8463, 10.1128/JVI.72.11.8463-8471.1998 · DOI · Paper page
  20. Durocher, 1997, The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors, The EMBO Journal, 16, 5687, 10.1093/emboj/16.18.5687 · DOI
  21. Durocher, 1996, The atrial natriuretic factor promoter is a downstream target for Nkx-2.5 in the myocardium, Molecular and Cellular Biology, 16, 4648, 10.1128/MCB.16.9.4648 · DOI
  22. Edgar, 2002, Gene Expression Omnibus: NCBI gene expression and hybridization array data repository, Nucleic Acids Research, 30, 207, 10.1093/nar/30.1.207 · DOI · Paper page
  23. Elliott, 2010, NK-2 class homeodomain proteins: conserved regulators of cardiogenesis, 10.1016/B978-0-12-381332-9.00026-8 · DOI
  24. Elliott, 2006, A tyrosine-rich domain within homeodomain transcription factor Nkx2-5 is an essential element in the early cardiac transcriptional regulatory machinery, Development, 133, 1311, 10.1242/dev.02305 · DOI
  25. Flicek, 2012, Ensembl 2012, Nucleic Acids Research, 40, D84, 10.1093/nar/gkr991 · DOI
  26. Frith, 2004, Detection of functional DNA motifs via statistical over-representation, Nucleic Acids Research, 32, 1372, 10.1093/nar/gkh299 · DOI
  27. Gautier, 2004, affy–analysis of Affymetrix GeneChip data at the probe level, Bioinformatics, 20, 307, 10.1093/bioinformatics/btg405 · DOI
  28. Gutierrez-Roelens, 2002, Progressive AV-block and anomalous venous return among cardiac anomalies associated with two novel missense mutations in the CSX/NKX2-5 gene, Human Mutation, 20, 75, 10.1002/humu.9041 · DOI
  29. Halfon, 2000, Ras pathway specificity is determined by the integration of multiple signal-activated and tissue-restricted transcription factors, Cell, 103, 63, 10.1016/S0092-8674(00)00105-7 · DOI
  30. Haudry, 2010, Using Trawler_standalone to discover overrepresented motifs in DNA and RNA sequences derived from various experiments including chromatin immunoprecipitation, Nature Protocols, 5, 323, 10.1038/nprot.2009.158 · DOI
  31. He, 2011, Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart, Proceedings of the National Academy of Sciences of USA, 108, 5632, 10.1073/pnas.1016959108 · DOI
  32. Holler, 2010, Targeted deletion of Hand2 in cardiac neural crest-derived cells influences cardiac gene expression and outflow tract development, Developmental biology, 341, 291, 10.1016/j.ydbio.2010.02.001 · DOI
  33. Huang da, 2009, Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources, Nature Protocols, 4, 44, 10.1038/nprot.2008.211 · DOI · Paper page
  34. Huang da, 2007, DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists, Nucleic Acids Research, 35, W169, 10.1093/nar/gkm415 · DOI
  35. Hulsen, 2008, BioVenn—a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams, BMC Genomics, 9, 488, 10.1186/1471-2164-9-488 · DOI
  36. Ieda, 2010, Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors, Cell, 142, 375, 10.1016/j.cell.2010.07.002 · DOI · Paper page
  37. Ikeda, 2002, Novel point mutation in the cardiac transcription factor CSX/NKX2.5 associated with congenital heart disease, Circulation Journal, 66, 561, 10.1253/circj.66.561 · DOI
  38. Ji, 2008, An integrated software system for analyzing ChIP-chip and ChIP-seq data, Nature Biotechnology, 26, 1293, 10.1038/nbt.1505 · DOI
  39. Ji, 2005, TileMap: create chromosomal map of tiling array hybridizations, Bioinformatics, 21, 3629, 10.1093/bioinformatics/bti593 · DOI
  40. Jin, 2013, Genome-wide screens for in vivo Tinman binding sites identify cardiac enhancers with diverse functional architectures, PLOS Genetics, 9, e1003195, 10.1371/journal.pgen.1003195 · DOI
  41. Kasahara, 2004, Biochemical analyses of eight NKX2.5 homeodomain missense mutations causing atrioventricular block and cardiac anomalies, Cardiovascular Research, 64, 40, 10.1016/j.cardiores.2004.06.004 · DOI
  42. Kasahara, 1999, Identification of the in vivo casein kinase II phosphorylation site within the homeodomain of the cardiac tisue-specifying homeobox gene product Csx/Nkx2.5, Molecular and Cellular Biology, 19, 526, 10.1128/MCB.19.1.526 · DOI
  43. Kasahara, 2000, Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease, The Journal of Clinical Investigation, 106, 299, 10.1172/JCI9860 · DOI
  44. Kattman, 2011a, Stem cells and their derivatives: a renaissance in cardiovascular translational research, Journal of Cardiovascular Translational Research, 4, 66, 10.1007/s12265-010-9235-1 · DOI
  45. Kaur, 2013, Probing transcription factor diffusion dynamics in the living mammalian embryo with photoactivatable fluorescence correlation spectroscopy, Nature Communications, 4, 1637, 10.1038/ncomms2657 · DOI
  46. Kent, 2002, The human genome browser at UCSC, Genome Research, 12, 996, 10.1101/gr.229102 · DOI · Paper page
  47. Killcoyne, 2009, Cytoscape: a community-based framework for network modeling, Methods in Molecular Biology, 563, 219, 10.1007/978-1-60761-175-2_12 · DOI
  48. Lavaur, 2007, A TAT-DEF-Elk-1 peptide regulates the cytonuclear trafficking of Elk-1 and controls cytoskeleton dynamics, The Journal of Neuroscience, 27, 14448, 10.1523/JNEUROSCI.2279-07.2007 · DOI
  49. Lin, 2006, Erm/thyroid transcription factor 1 interactions modulate surfactant protein C transcription, The Journal of Biological Chemistry, 281, 16716, 10.1074/jbc.M602221200 · DOI
  50. Ling, 1998, Interaction of transcription factors with serum response factor. Identification of the Elk-1 binding surface, The Journal of Biological Chemistry, 273, 10506, 10.1074/jbc.273.17.10506 · DOI
  51. Longabaugh, 2009, Visualization, documentation, analysis, and communication of large-scale gene regulatory networks, Biochimica et Biophysica Acta, 1789, 363, 10.1016/j.bbagrm.2008.07.014 · DOI
  52. Mace, 2009, Transcriptional remodeling of rapidly stimulated HL-1 atrial myocytes exhibits concordance with human atrial fibrillation, Journal of Molecular and Cellular Cardiology, 47, 485, 10.1016/j.yjmcc.2009.07.006 · DOI
  53. Moorman, 2006, Hotspots of transcription factor colocalization in the genome of Drosophila melanogaster, Proceedings of the National Academy of Sciences of USA, 103, 12027, 10.1073/pnas.0605003103 · DOI
  54. Mori, 2006, Tbx5-dependent rheostatic control of cardiac gene expression and morphogenesis, Developmental Biology, 297, 566, 10.1016/j.ydbio.2006.05.023 · DOI
  55. Narlikar, 2010, Genome-wide discovery of human heart enhancers, Genome Research, 20, 381, 10.1101/gr.098657.109 · DOI
  56. Negre, 2006, Chromosomal distribution of PcG proteins during Drosophila development, PLOS Biology, 4, e170, 10.1371/journal.pbio.0040170 · DOI
  57. Pavesi, 2006, Using Weeder for the discovery of conserved transcription factor binding sites, Current Protocols in Bioinformatics, 10.1002/0471250953.bi0211s15 · DOI
  58. Pham, 2007, Combinatorial function of ETS transcription factors in the developing vasculature, Developmental Biology, 303, 772, 10.1016/j.ydbio.2006.10.030 · DOI
  59. Prall, 2007, An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation, Cell, 128, 947, 10.1016/j.cell.2007.01.042 · DOI
  60. Quinlan, 2010, BEDTools: a flexible suite of utilities for comparing genomic features, Bioinformatics, 26, 841, 10.1093/bioinformatics/btq033 · DOI · Paper page
  61. Riazi, 2009, NKX2-5 regulates the expression of beta-catenin and GATA4 in ventricular myocytes, PLOS ONE, 4, e5698, 10.1371/journal.pone.0005698 · DOI
  62. Rojas, 2008, GATA4 is a direct transcriptional activator of cyclin D2 and Cdk4 and is required for cardiomyocyte proliferation in anterior heart field-derived myocardium, Molecular and Cellular Biology, 28, 5420, 10.1128/MCB.00717-08 · DOI
  63. Schachterle, 2011, ETS-dependent regulation of a distal Gata4 cardiac enhancer, Developmental Biology, 361, 439, 10.1016/j.ydbio.2011.10.023 · DOI
  64. Schlesinger, 2011, The cardiac transcription network modulated by Gata4, Mef2a, Nkx2.5, Srf, histone modifications, and microRNAs, PLOS Genetics, 7, e1001313, 10.1371/journal.pgen.1001313 · DOI
  65. Shen, 2011, Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function, The Journal of Clinical Investigation, 121, 4640, 10.1172/JCI59472 · DOI
  66. Silvestri, 2008, Genome-wide identification of Smad/Foxh1 targets reveals a role for Foxh1 in retinoic acid regulation and forebrain development, Developmental Cell, 14, 411, 10.1016/j.devcel.2008.01.004 · DOI
  67. Stefan, 2007, Quantification of dynamic protein complexes using Renilla luciferase fragment complementation applied to protein kinase A activities in vivo, Proceedings of the National Academy of Sciences of USA, 104, 16916, 10.1073/pnas.0704257104 · DOI
  68. Teytelman, 2013, Highly expressed loci are vulnerable to misleading ChIP localization of multiple unrelated proteins, Proceedings of the National Academy of Sciences of USA, 110, 18602, 10.1073/pnas.1316064110 · DOI · Paper page
  69. Tolhuis, 2006, Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster, Nature Genetics, 38, 694, 10.1038/ng1792 · DOI
  70. Treisman, 1994, Ternary complex factors: growth factor regulated transcriptional activators, Current Opinion in Genetics & Development, 4, 96, 10.1016/0959-437X(94)90097-3 · DOI
  71. Ueyama, 2003, Myocardin expression is regulated by Nkx2.5, and its function is required for cardiomyogenesis, Molecular and Cellular Biology, 23, 9222, 10.1128/MCB.23.24.9222-9232.2003 · DOI
  72. van Bemmel, 2010, The insulator protein SU(HW) fine-tunes nuclear lamina interactions of the Drosophila genome, PLOS ONE, 5, e15013, 10.1371/journal.pone.0015013 · DOI
  73. van Bueren, 2010, Hes1 expression is reduced in Tbx1 null cells and is required for the development of structures affected in 22q11 deletion syndrome, Developmental Biology, 340, 369, 10.1016/j.ydbio.2010.01.020 · DOI
  74. van den Boogaard, 2012, Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer, The Journal of Clinical Investigation, 122, 2519, 10.1172/JCI62613 · DOI
  75. van Steensel, 2001, Chromatin profiling using targeted DNA adenine methyltransferase, Nature Genetics, 27, 304, 10.1038/85871 · DOI
  76. van Steensel, 2000, Identification of in vivo DNA targets of chromatin proteins using tethered dam methyltransferase, Nature Biotechnology, 18, 424, 10.1038/74487 · DOI
  77. Vogel, 2006, Human heterochromatin proteins form large domains containing KRAB-ZNF genes, Genome Research, 16, 1493, 10.1101/gr.5391806 · DOI
  78. Vogel, 2007, Detection of in vivo protein-DNA interactions using DamID in mammalian cells, Nature Protocols, 2, 1467, 10.1038/nprot.2007.148 · DOI
  79. von Both, 2004, Foxh1 is essential for development of the anterior heart field, Developmental Cell, 7, 331, 10.1016/j.devcel.2004.07.023 · DOI
  80. Waldminghaus, 2010, ChIP on Chip: surprising results are often artifacts, BMC Genomics, 11, 414, 10.1186/1471-2164-11-414 · DOI
  81. Watanabe, 2012, Fibroblast growth factor 10 gene regulation in the second heart field by Tbx1, Nkx2-5, and Islet1 reveals a genetic switch for down-regulation in the myocardium, Proceedings of the National Academy of Sciences of USA, 109, 18273, 10.1073/pnas.1215360109 · DOI
  82. Weiler, 1998, Site-directed mutations in the vnd/NK-2 homeodomain. Basis of variations in structure and sequence-specific DNA binding, The Journal of Biological Chemistry, 273, 10994, 10.1074/jbc.273.18.10994 · DOI
  83. Willems, 2011, Small-molecule inhibitors of the Wnt pathway potently promote cardiomyocytes from human embryonic stem cell-derived mesoderm, Circulation Research, 109, 360, 10.1161/CIRCRESAHA.111.249540 · DOI
  84. Woznica, 2012, Initial deployment of the cardiogenic gene regulatory network in the basal chordate, Ciona intestinalis, Developmental Biology, 368, 127, 10.1016/j.ydbio.2012.05.002 · DOI
  85. Yang, 2014, Leveraging biological replicates to improve analysis in ChIP-seq experiments, Computational and Structural Biotechnology Journal, 9, e201401002, 10.5936/csbj.201401002 · DOI
  86. Yin, 2011, A high-resolution whole-genome map of key chromatin modifications in the adult Drosophila melanogaster, PLOS Genetics, 7, e1002380, 10.1371/journal.pgen.1002380 · DOI
  87. Zacher, 2010, Starr: simple tiling ARRay analysis of affymetrix chip-chip data, BMC Bioinformatics, 11, 194, 10.1186/1471-2105-11-194 · DOI

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Metadata

Authors
Bouveret, R., Waardenberg, A. J., Schonrock, N., Ramialison, M., Doan, T., de Jong, D., Bondue, A., Kaur, G., Mohamed, S., Fonoudi, H., Chen, C.-M., Wouters, M. A., Bhattacharya, S., Plachta, N., Dunwoodie, S. L., Chapman, G., Blanpain, C., & Harvey, R. P.
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2015-07-06
Volume
4
ISSN
2050-084X
DOI
10.7554/elife.06942
PMC
PMC4548209
Cited by
57
References
6
Language
en
Licence
Funders
  • National Health and Medical Research Council (NHMRC) (1061539, 573732, 573703, 1052171, 514900, 1042002, 573705)
  • Atlantic Philanthropies (19131)
  • British Heart Foundation (CH/09/003)
  • Wellcome Trust (083228)
  • Schweizerische Nationalfonds zur Förderung der Wissenschaftlichen Forschung (PBEZB-111553)
  • Australian Research Council (ARC) (DP0988507, DP120104594, DE120100794)
  • European Molecular Biology Organization (EMBO) (1133-2009)
  • Human Frontier Science Program (HFSP) (LT00044/2007-L, LT000245/2010-L)
  • National Heart Foundation of Australia (1049980)

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