Genes Integrate and Hedgehog Pathways in the Second Heart Field for Cardiac Septation

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Atrioventricular septal defects (AVSDs) are a common severe class of congenital heart defects. Recent work demonstrates that events in the second heart field (SHF) progenitors, rather than in the heart, drive atrioventricular (AV) septation. Our laboratory has shown that both Hedgehog signaling and the T-box transcription factor, Tbx5, are required in the SHF for AV septation. To understand the molecular underpinnings of the AV septation process we investigated SHF Hedgehog-dependent gene regulatory networks. Transcriptional profiling and chromatin interaction assays identified the Forkhead box transcription factors Foxf1a and Foxf2 as SHF Hedgehog targets. Compound haploinsufficiency for Foxf1a and Foxf2 caused AVSDs in mice, demonstrating the biological relevance of this pathway. We identified a cis-regulatory element at Foxf1a that bound TBX5 and Hedgehog transcriptional regulators GLI1 and GLI3 in-vivo. Furthermore, TBX5 and Gli1 co-activate transcription of the identified cis-regulatory element in-vitro. The enhancer is expressed primarily in the pSHF in-vivo, where Tbx5 and Gli1 expression overlap. Our findings implicate Foxf1a and Foxf2 in AV septation and establish Tbx5 and Hedgehog signaling upstream of Foxf genes in a gene regulatory network for cardiac septation.

Vyšlo v časopise: Genes Integrate and Hedgehog Pathways in the Second Heart Field for Cardiac Septation. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004604
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004604

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Zdroje

1. MommersteegMT, SoufanAT, de LangeFJ, van den HoffMJ, AndersonRH, et al. (2006) Two distinct pools of mesenchyme contribute to the development of the atrial septum. Circ Res 99: 351–3.

2. SnarrBS, O'NealJL, ChintalapudiMR, WirrigEE, PhelpsAL, et al. (2007) Isl1 expression at the venous pole identifies a novel role for the second heart field in cardiac development. Circ Res 101: 971–4.

3. SnarrBS, WirrigEE, PhelpsAL, TruskTC, WesselsA (2007) A spatiotemporal evaluation of the contribution of the dorsal mesenchymal protrusion to cardiac development. Dev Dyn 236: 1287–94.

4. GoddeerisMM, RhoS, PetietA, DavenportCL, Johnson, et al. (2008) Intracardiac septation requires hedgehog-dependent cellular contributions from outside the heart. Development 135: 1887–1895.

5. HoffmannAD, PetersonMA, Friedland-LittleJM, AndersonSA, MoskowitzIP (2009) sonic hedgehog is required in pulmonary endoderm for atrial septation. Development 136: 1761–1770.

6. XieL, HoffmannAD, Burnicka-TurekO, Friedland-LittleJM, ZhangK, et al. (2012) Tbx5-hedgehog molecular networks are essential in the second heart field for atrial septation. Dev Cell 23: 280–91.

7. Nüsslein-VolhardC, WieschausE (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287: 795–801.

8. InghamPW, McMahonAP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15: 3059–87.

9. ZhangXM, Ramalho-SantosM, McMahonAP (2001) Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell 106: 781–92.

10. Washington SmoakI, ByrdNA, Abu-IssaR, GoddeerisMM, AndersonR, et al. (2005) Sonic hedgehog is required for cardiac outflow tract and neural crest cell development. Dev Biol 283: 357–72.

11. BassonCT, BachinskyDR, LinRC, LeviT, ElkinsJA, et al. (1997) Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 15: 30–35.

12. GargV, KathiriyaIS, BarnesR, SchlutermanMK, KingIN, et al. (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424: 443–447.

13. LiQY, Newbury-EcobRA, TerrettJA, WilsonDI, CurtisAR, et al. (1997) Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet 15: 21–29.

14. SchottJJ, BensonDW, BassonCT, PeaseW, SilberbachGM, et al. (1998) Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281: 108–111.

15. BruneauBG, NemerG, SchmittJP, CharronF, RobitailleL, 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: 709–21.

16. HiroiY, KudohS, MonzenK, IkedaY, YazakiY, et al. (2001) Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nat Genet 28: 276–280.

17. TakeuchiJK, BruneauBG (2009) Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459: 708–711.

18. GoetzSC, BrownDD, ConlonFL (2006) TBX5 is required for embryonic cardiac cell cycle progression. Development 133: 2575–84.

19. ZhuY, GramoliniAO, WalshMA, ZhouYQ, SlorachC, et al. (2008) Tbx5-dependent pathway regulating diastolic function in congenital heart disease. Proc Natl Acad Sci U S A 105: 5519–24.

20. ArnoldsDE, LiuF, FahrenbachJP, KimGH, SchillingerKJ, et al. (2012) TBX5 drives Scn5a expression to regulate cardiac conduction system function. J Clin Invest 122: 2509–18.

21. MoriAD, ZhuY, VahoraI, NiemanB, Koshiba-TakeuchiK, et al. (2006) Tbx5-dependent rheostatic control of cardiac gene expression and morphogenesis. Dev Biol 297: 566–86.

22. FalconS, GentlemanR (2007) Using GOstats to test gene lists for GO term association. Bioinformatics 23: 257–258.

23. VokesSA, JiH, WongWH, McMahonAP (2008) A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb. Genes Dev 22: 2651–63.

24. VerziMP, McCulleyDJ, De ValS, DodouE, BlackBL (2005) The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary/anterior heart field. Dev Biol 287: 134–45.

25. ZhangY, LiuT, MeyerCA, EeckhouteJ, JohnsonDS, et al. (2008) Model-based analysis of ChIP-Seq (MACS). Genome Biol 9: R137.

26. HeintzmanND, RenB (2009) Finding distal regulatory elements in the human genome. Curr Opin Genet Dev 19: 541–9.

27. ViselA, RubinEM, PennacchioLA (2009) Genomic views of distant-acting enhancers. Nature 461: 199–205.

28. HusainA, ZhangX, DollMA, StatesJC, BarkerDF, et al. (2007) Functional analysis of the human N-acetyltransferase 1 major promoter: quantitation of tissue expression and identification of critical sequence elements. Drug Metab Dispos 35: 1649–56.

29. SanyalA, LajoieBR, JainG, DekkerJ (2012) The long-range interaction landscape of gene promoters. Nature 489: 109–13.

30. HeinzS, BennerC, SpannN, BertolinoE, LinYC, et al. (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38: 576–589.

31. MatysV, Kel-MargoulisOV, FrickeE, LiebichI, LandS, et al. (2006) TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucleic Acids Res 34: D108–110.

32. OrmestadM, AstorgaJ, LandgrenH, WangT, JohanssonBR, et al. (2006) Foxf1 and Foxf2 control murine gut development by limiting mesenchymal Wnt signaling and promoting extracellular matrix production. Development 133: 833–43.

33. HeA, KongSW, MaQ, PuWT (2011) Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart. Proc Natl Acad Sci U S A 108: 5632–7.

34. GroteP, WittlerL, HendrixD, KochF, WährischS, et al. (2013) The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev Cell 24: 206–14.

35. KotharyR, ClapoffS, DarlingS, PerryMD, MoranLA, et al. (1989) Inducible expression of an hsp68-lacZ hybrid gene in transgenic mice. Development 105: 707–14.

36. MadisonBB, McKennaLB, DolsonD, EpsteinDJ, KaestnerKH (2008) FoxF1 and FoxL1 link hedgehog signaling and the control of epithelial proliferation in the developing stomach and intestine. J Biol Chem 284: 5936–44.

37. MahlapuuM, EnerbäckS, CarlssonP (2001) Haploinsufficiency of the forkhead gene Foxf1, a target for sonic hedgehog signaling, causes lung and foregut malformations. Development 128: 2397–406.

38. BehJ, ShiW, LevineM, DavidsonB, ChristiaenL (2007) FoxF is essential for FGF-induced migration of heart progenitor cells in the ascidian Ciona intestinalis. Development 134: 3297–305.

39. ChristiaenL, DavidsonB, KawashimaT, PowellW, NollaH, et al. (2008) The transcription/migration interface in heart precursors of Ciona intestinalis. Science 320: 1349–52.

40. VokesSA, JiH, McCuineS, TenzenT, GilesS, et al. (2007) Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development 134: 1977–89.

41. GentlemanRC, CareyVJ, BatesDM, BolstadB, DettlingM, et al. (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5: R80.

42. HuberW, von HeydebreckA, SültmannH, PoustkaA, VingronM (2002) Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics 18 Suppl 1: S96–104.

43. LangerW, SohlerF, LederG, BeckmannG, SeidelH, et al. (2010) Exon array analysis using re-defined probe sets results in reliable identification of alternatively spliced genes in non-small cell lung cancer. BMC Genomics 11: 676.

44. TusherVG, TibshiraniR, ChuG (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 98: 5116–5121.

45. MoormanAF, HouwelingAC, de BoerPA, ChristoffelsVM (2001) Sensitive nonradioactive detection of mRNA in tissue sections: novel application of the whole-mount in situ hybridization protocol. J Histochem Cytochem 49: 1–8.