A Discrete Transition Zone Organizes the Topological and Regulatory Autonomy of the Adjacent and Genes

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The specificity of enhancer-gene interactions is fundamental to the execution of gene regulatory programs underpinning embryonic development and cell differentiation. However, our understanding of the mechanisms conferring specificity to enhancers and target gene interactions is limited. In this study, we characterize the cis-regulatory organization of a large genomic locus consisting of two developmental genes, Tfap2c and Bmp7. We show that this locus is structurally partitioned into two distinct domains by the constitutive action of a discrete transition zone located between the two genes. This separation restricts selectively the functional action of enhancers to the genes present within the same domain. Interestingly, the effects of this region as a boundary are relative, as it allows some competing interactions to take place across domains. We show that these interactions modulate the functional output of a brain enhancer on its primary target gene resulting in the spatial restriction of its expression domain. These results support a functional link between topological chromatin domains and allocation of enhancers to genes. They further show that a precise adjustment of chromatin interaction levels fine-tunes gene regulation by long-range enhancers.

Vyšlo v časopise: A Discrete Transition Zone Organizes the Topological and Regulatory Autonomy of the Adjacent and Genes. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004897
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004897

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

2. SakabeNJ, SavicD, NobregaMA (2012) Transcriptional enhancers in development and disease. Genome Biol 13: 238.

3. De GobbiM (2006) A Regulatory SNP Causes a Human Genetic Disease by Creating a New Transcriptional Promoter. Science 312: 1215–1217.

4. MontavonT, ThevenetL, DubouleD (2012) Impact of copy number variations (CNVs) on long-range gene regulation at the HoxD locus. Proc Natl Acad Sci U S A 109: 20204–20211.

5. PeichelCL, PrabhakaranB, VogtTF (1997) The mouse Ulnaless mutation deregulates posterior HoxD gene expression and alters appendicular patterning. Development 124: 3481–3492.

6. KokubuC, WilmB, KokubuT, WahlM, RodrigoI, et al. (2003) Undulated short-tail deletion mutation in the mouse ablates Pax1 and leads to ectopic activation of neighboring Nkx2-2 in domains that normally express Pax1. Genetics 165: 299–307.

7. MarinićM, AktasT, RufS, SpitzF (2013) An integrated holo-enhancer unit defines tissue and gene specificity of the Fgf8 regulatory landscape. Dev Cell 24: 530–542.

8. LetticeLA, DanielsS, SweeneyE, VenkataramanS, DevenneyPS, et al. (2011) Enhancer-adoption as a mechanism of human developmental disease. Hum Mutat 32: 1492–1499.

9. SpitzF, GonzalezF, DubouleD (2003) A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell 113: 405–417.

10. SpielmannM, BrancatiF, KrawitzPM, RobinsonPN, IbrahimDM, et al. (2012) Homeotic Arm-to-Leg Transformation Associated with Genomic Rearrangements at the PITX1 Locus. Am J of Hum Genet 91: 629–635.

11. KlopockiE, LohanS, BrancatiF, KollR, BrehmA, et al. (2011) Copy-number variations involving the IHH locus are associated with syndactyly and craniosynostosis. Am J Hum Genet 88: 70–75.

12. GostissaM, YanCT, BiancoJM, CognéM, PinaudE, et al. (2009) Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3' regulatory region. Nature 462: 803–807.

13. BanerjiJ, RusconiS, SchaffnerW (1981) Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences. Cell 27: 299–308.

14. RufS, SymmonsO, UsluVV, DolleD, HotC, et al. (2011) Large-scale analysis of the regulatory architecture of the mouse genome with a transposon-associated sensor. Nat Genet 43: 379–386.

15. SymmonsO, UsluVV, TsujimuraT, RufS, NassariS, et al. (2014) Functional and topological characteristics of mammalian regulatory domains. Genome Res 24: 390–400.

16. JinL, LongL, GreenMA, SpearBT (2009) The alpha-fetoprotein enhancer region activates the albumin and alpha-fetoprotein promoters during liver development. Dev Biol 336: 294–300.

17. NickolJM, FelsenfeldG (1988) Bidirectional control of the chicken beta- and epsilon-globin genes by a shared enhancer. Proc Natl Acad Sci USA 85: 2548–2552.

18. SpitzF, HerkenneC, MorrisMA, DubouleD (2005) Inversion-induced disruption of the Hoxd cluster leads to the partition of regulatory landscapes. Nat Genet 37: 889–893.

19. TsujimuraT, HosoyaT, KawamuraS (2010) A Single Enhancer Regulating the Differential Expression of Duplicated Red-Sensitive Opsin Genes in Zebrafish. PLoS Genet 6: e1001245.

20. SumiyamaK, IrvineSQ, StockDW, WeissKM, KawasakiK, et al. (2002) Genomic structure and functional control of the Dlx3–7 bigene cluster. Proc Natl Acad Sci USA 99: 780–785.

21. XuX, ScottMM, DenerisES (2006) Shared long-range regulatory elements coordinate expression of a gene cluster encoding nicotinic receptor heteromeric subtypes. Mol Cell Biol 26: 5636–5649.

22. CarvajalJJ, CoxD, SummerbellD, RigbyPW (2001) A BAC transgenic analysis of the Mrf4/Myf5 locus reveals interdigitated elements that control activation and maintenance of gene expression during muscle development. Development 128: 1857–1868.

23. ZunigaA, MichosO, SpitzF, HaramisA-PG, PanmanL, et al. (2004) Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expression. Genes Dev 18: 1553–1564.

24. CajiaoI, ZhangA, YooEJ, CookeNE, LiebhaberSA (2004) Bystander gene activation by a locus control region. EMBO J 23: 3854–3863.

25. LowerKM, HughesJR, De GobbiM, HendersonS, ViprakasitV, et al. (2009) Adventitious changes in long-range gene expression caused by polymorphic structural variation and promoter competition. Proc Natl Acad Sci U S A 106: 21771–21776.

26. CalhounVC, LevineM (2003) Long-range enhancer-promoter interactions in the Scr-Antp interval of the Drosophila Antennapedia complex. Proc Natl Acad Sci USA 100: 9878–9883.

27. OhtsukiS, LevineM, CaiHN (1998) Different core promoters possess distinct regulatory activities in the Drosophila embryo. Genes Dev 12: 547–556.

28. CaiH, LevineM (1995) Modulation of enhancer-promoter interactions by insulators in the Drosophila embryo. Nature 376: 533–536 doi:10.1038/376533a0

29. GeyerPK, CorcesVG (1992) DNA position-specific repression of transcription by a Drosophila zinc finger protein. Genes Dev 6: 1865–1873.

30. KellumR, SchedlP (1992) A group of scs elements function as domain boundaries in an enhancer-blocking assay. Mol Cell Biol 12: 2424–2431.

31. YangJ, CorcesVG (2011) Chromatin insulators: a role in nuclear organization and gene expression. Adv Cancer Res 110: 43–76.

32. ChetverinaD, AokiT, ErokhinM, GeorgievP, SchedlP (2014) Making connections: Insulators organize eukaryotic chromosomes into independent cis-regulatory networks. Bioessays 36: 163–172.

33. DekkerJ, Marti-RenomMA, MirnyLA (2013) Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat Rev Genet 14: 390–403.

34. DixonJR, SelvarajS, YueF, KimA, LiY, et al. (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485: 376–380.

35. NoraEP, LajoieBR, SchulzEG, GiorgettiL, OkamotoI, et al. (2012) Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485: 381–385.

36. NoraEP, DekkerJ, HeardE (2013) Segmental folding of chromosomes: a basis for structural and regulatory chromosomal neighborhoods? Bioessays 35: 818–828.

37. GibcusJH, DekkerJ (2013) The Hierarchy of the 3D Genome. Mol Cell 49: 773–782.

38. ShenY, YueF, McClearyDF, YeZ, EdsallL, et al. (2012) A map of the cis-regulatory sequences in the mouse genome. Nature 488: 116–120.

39. AndreyG, MontavonT, MascrezB, GonzalezF, NoordermeerD, et al. (2013) A switch between topological domains underlies HoxD genes collinearity in mouse limbs. Science 340: 1234167.

40. JinF, LiY, DixonJR, SelvarajS, YeZ, et al. (2013) A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 503: 290–294.

41. Phillips-CreminsJE, SauriaMEG, SanyalA, GerasimovaTI, LajoieBR, et al. (2013) Architectural Protein Subclasses Shape 3D Organization of Genomes during Lineage Commitment. Cell 153: 1281–1295.

42. ChazaudC, Oulad-AbdelghaniM, BouilletP, DécimoD, ChambonP, et al. (1996) AP-2.2, a novel gene related to AP-2, is expressed in the forebrain, limbs and face during mouse embryogenesis. Mech Dev 54: 83–94.

43. HofmannC, LuoG, BallingR, KarsentyG (1996) Analysis of limb patterning in BMP-7-deficient mice. Dev Genet 19: 43–50.

44. FurutaY, PistonDW, HoganBL (1997) Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development. Development 124: 2203–2212.

45. ZhaoF, LufkinT, GelbBD (2003) Expression of Tfap2d, the gene encoding the transcription factor Ap-2 delta, during mouse embryogenesis. Gene Expr Patterns 3: 213–217.

46. GrayPA, FuH, LuoP, ZhaoQ, YuJ, et al. (2004) Mouse brain organization revealed through direct genome-scale TF expression analysis. Science 306: 2255–2257.

47. ZouvelouV, LuderH-U, MitsiadisTA, GrafD (2009) Deletion of BMP7 affects the development of bones, teeth, and other ectodermal appendages of the orofacial complex. Journal of experimental zoology Part B, Molecular and developmental evolution. 312B: 361–374 d.

48. DaneshSM, VillasenorA, ChongD, SoukupC, CleaverO (2009) BMP and BMP receptor expression during murine organogenesis. Gene Expr Patterns 9: 255–265.

49. AkalinA, FredmanD, ArnerE, DongX, BryneJC, et al. (2009) Transcriptional features of genomic regulatory blocks. Genome Biol 10: R38.

50. YeeSP, RigbyPW (1993) The regulation of myogenin gene expression during the embryonic development of the mouse. Genes Dev 7: 1277–1289.

51. StrykeD, KawamotoM, HuangCC, JohnsSJ, KingLA, et al. (2003) BayGenomics: a resource of insertional mutations in mouse embryonic stem cells. Nucleic Acids Res 31: 278–281.

52. KondoT, DubouleD (1999) Breaking colinearity in the mouse HoxD complex. Cell 97: 407–417.

53. AdamsD, KarolakM, RobertsonE, OxburghL (2007) Control of kidney, eye and limb expression of Bmp7 by an enhancer element highly conserved between species. Developmental biology 311: 679–690.

54. HéraultY, RassoulzadeganM, CuzinF, DubouleD (1998) Engineering chromosomes in mice through targeted meiotic recombination (TAMERE). Nat Genet 20: 381–384.

55. NordAS, BlowMJ, AttanasioC, AkiyamaJA, HoltA, et al. (2013) Rapid and pervasive changes in genome-wide enhancer usage during mammalian development. Cell 155: 1521–1531.

56. ViselA, TaherL, GirgisH, MayD, GolonzhkaO, et al. (2013) A High-Resolution Enhancer Atlas of the Developing Telencephalon. Cell 152: 895–908.

57. BlowMJ, McCulleyDJ, LiZ, ZhangT, AkiyamaJA, et al. (2010) ChIP-Seq identification of weakly conserved heart enhancers. Nat Genet 42: 806–810.

58. ViselA, MinovitskyS, DubchakI, PennacchioLA (2007) VISTA Enhancer Browser—a database of tissue-specific human enhancers. Nucleic Acids Res 35: D88–D92.

59. HuberW, ToedlingJ, SteinmetzLM (2006) Transcript mapping with high-density oligonucleotide tiling arrays. Bioinformatics 22: 1963–1970.

60. NolisIK, McKayDJ, MantouvalouE, LomvardasS, MerikaM, et al. (2009) Transcription factors mediate long-range enhancer-promoter interactions. Proc Natl Acad Sci U S A 106: 20222–20227.

61. TanimotoK, LiuQ, BungertJ, EngelJD (1999) Effects of altered gene order or orientation of the locus control region on human beta-globin gene expression in mice. Nature 398: 344–348.

62. KmitaM, FraudeauN, HéraultY, DubouleD (2002) Serial deletions and duplications suggest a mechanism for the collinearity of Hoxd genes in limbs. Nature 420: 145–150.

63. ParkJ-S, MaW, O'BrienLL, ChungE, GuoJ-J, et al. (2012) Six2 and Wnt regulate self-renewal and commitment of nephron progenitors through shared gene regulatory networks. Dev Cell 23: 637–651.

64. MontavonT, SoshnikovaN, MascrezB, JoyeE, ThevenetL, et al. (2011) A regulatory archipelago controls Hox genes transcription in digits. Cell 147: 1132–1145.

65. DostieJ, RichmondTA, ArnaoutRA, SelzerRR, LeeWL, et al. (2006) Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res 16: 1299–1309.

66. Ghavi-HelmY, KleinFA, PakozdiT, CiglarL, NoordermeerD, et al. (2014) Enhancer loops appear stable during development and are associated with paused polymerase. Nature 512: 96–100.

67. PhillipsJE, CorcesVG (2009) CTCF: master weaver of the genome. Cell 137: 1194–1211.

68. MerkenschlagerM, OdomDT (2013) CTCF and cohesin: linking gene regulatory elements with their targets. Cell 152: 1285–1297.

69. SanyalA, LajoieBR, JainG, DekkerJ (2012) The long-range interaction landscape of gene promoters. Nature 489: 109–113.

70. ZuinJ, DixonJR, van der ReijdenMIJA, YeZ, KolovosP, et al. (2014) Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc Natl Acad Sci U S A 111: 996–1001.

71. SoshnikovaN, MontavonT, LeleuM, GaljartN, DubouleD (2010) Functional Analysis of CTCF During Mammalian Limb Development. Dev Cell 19: 819–830.

72. SchoenfelderS, SextonT, ChakalovaL, CopeNF, HortonA, et al. (2010) Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells. Nat Genet 42: 53–61.

73. LiG, RuanX, AuerbachRK, SandhuKS, ZhengM, et al. (2012) Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148: 84–98.

74. EichenlaubMP, EttwillerL (2011) De novo genesis of enhancers in vertebrates. PLoS Biol 9: e1001188.

75. GompelN, Prud'hommeB, WittkoppPJ, KassnerVA, CarrollSB (2005) Chance caught on the wing: cis-regulatory evolution and the origin of pigment patterns in Drosophila. Nature 433: 481–487.

76. FranchiniLF, López-LealR, NasifS, BeatiP, GelmanDM, et al. (2011) Convergent evolution of two mammalian neuronal enhancers by sequential exaptation of unrelated retroposons. Proc Natl Acad Sci U S A 108: 15270–15275.

77. PintoL, DrechselD, SchmidM-T, NinkovicJ, IrmlerM, et al. (2009) AP2gamma regulates basal progenitor fate in a region- and layer-specific manner in the developing cortex. Nat Neurosci 12: 1229–1237.

78. WittkoppPJ, KalayG (2012) Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence. Nat Rev Genet 13: 59–69.

79. ChenC-K, SymmonsO, UsluVV, TsujimuraT, RufS, et al. (2013) TRACER: a resource to study the regulatory architecture of the mouse genome. BMC Genomics 14: 215.

80. TangS-HE, SilvaFJ, TsarkWMK, MannJR (2002) A Cre/loxP-deleter transgenic line in mouse strain 129S1/SvImJ. Genesis 32: 199–202.

81. FriedliM, BardeI, ArcangeliM, VerpS, QuazzolaA, et al. (2010) A systematic enhancer screen using lentivector transgenesis identifies conserved and non-conserved functional elements at the Olig1 and Olig2 locus. PLoS ONE 5: e15741.

82. SplinterE, de WitE, van de WerkenHJG, KlousP, de LaatW (2012) Determining long-range chromatin interactions for selected genomic sites using 4C-seq technology: From fixation to computation. Methods 58: 221–230.

83. LangmeadB, TrapnellC, PopM, SalzbergSL (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10: R25.

84. DerrienT, EstelléJ, SolaSM, KnowlesDG, RaineriE, et al. (2012) Fast Computation and Applications of Genome Mappability. PLoS ONE 7: e30377.

85. AttanasioC, NordAS, ZhuY, BlowMJ, BiddieSC, et al. (2014) Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis. Genome Res 24: 920–929.

86. ViselA, BlowMJ, LiZ, ZhangT, AkiyamaJA, et al. (2009) ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457: 854–858.