The Enhancer Landscape during Early Neocortical Development Reveals Patterns of Dense Regulation and Co-option

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Genetic studies have identified a core set of transcription factors and target genes that control the development of the neocortex, the region of the human brain responsible for higher cognition. The specific regulatory interactions between these factors, many key upstream and downstream genes, and the enhancers that mediate all these interactions remain mostly uncharacterized. We perform p300 ChIP-seq to identify over 6,600 candidate enhancers active in the dorsal cerebral wall of embryonic day 14.5 (E14.5) mice. Over 95% of the peaks we measure are conserved to human. Eight of ten (80%) candidates tested using mouse transgenesis drive activity in restricted laminar patterns within the neocortex. GREAT based computational analysis reveals highly significant correlation with genes expressed at E14.5 in key areas for neocortex development, and allows the grouping of enhancers by known biological functions and pathways for further studies. We find that multiple genes are flanked by dozens of candidate enhancers each, including well-known key neocortical genes as well as suspected and novel genes. Nearly a quarter of our candidate enhancers are conserved well beyond mammals. Human and zebrafish regions orthologous to our candidate enhancers are shown to most often function in other aspects of central nervous system development. Finally, we find strong evidence that specific interspersed repeat families have contributed potentially key developmental enhancers via co-option. Our analysis expands the methodologies available for extracting the richness of information found in genome-wide functional maps.

Vyšlo v časopise: The Enhancer Landscape during Early Neocortical Development Reveals Patterns of Dense Regulation and Co-option. PLoS Genet 9(8): e32767. doi:10.1371/journal.pgen.1003728
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003728

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Zdroje

1. HollandLZ (2009) Chordate roots of the vertebrate nervous system: expanding the molecular toolkit. Nature reviews Neuroscience 10 : 736–746.

2. MolnarZ (2011) Evolution of cerebral cortical development. Brain, behavior and evolution 78 : 94–107.

3. JarvisED, GunturkunO, BruceL, CsillagA, KartenH, et al. (2005) Avian brains and a new understanding of vertebrate brain evolution. Nat Rev Neurosci 6 : 151–159.

4. LuiJH, HansenDV, KriegsteinAR (2011) Development and evolution of the human neocortex. Cell 146 : 18–36.

5. RubensteinJL (2011) Annual Research Review: Development of the cerebral cortex: implications for neurodevelopmental disorders. Journal of child psychology and psychiatry, and allied disciplines 52 : 339–355.

6. KwanKY, SestanN, AntonES (2012) Transcriptional co-regulation of neuronal migration and laminar identity in the neocortex. Development 139 : 1535–1546.

7. MolyneauxBJ, ArlottaP, MenezesJR, MacklisJD (2007) Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci 8 : 427–437.

8. ShimS, KwanKY, LiM, LefebvreV, SestanN (2012) Cis-regulatory control of corticospinal system development and evolution. Nature 486 : 74–79.

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

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

11. McLeanCY, BristorD, HillerM, ClarkeSL, SchaarBT, et al. (2010) GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol 28 : 495–501.

12. FingerJH, SmithCM, HayamizuTF, McCrightIJ, EppigJT, et al. (2011) The mouse Gene Expression Database (GXD): 2011 update. Nucleic acids research 39: D835–841.

13. Kaufman MH (1992) The atlas of mouse development. London ; San Diego: Academic Press. xvi, 512 p. p.

14. AyoubAE, OhS, XieY, LengJ, CotneyJ, et al. (2011) Transcriptional programs in transient embryonic zones of the cerebral cortex defined by high-resolution mRNA sequencing. Proc Natl Acad Sci U S A 108 : 14950–14955.

15. ViselA, TaherL, GirgisH, MayD, GolonzhkaO, et al. (2013) A high-resolution enhancer atlas of the developing telencephalon. Cell 152 : 895–908.

16. KimTK, HembergM, GrayJM, CostaAM, BearDM, et al. (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465 : 182–187.

17. MayD, BlowMJ, KaplanT, McCulleyDJ, JensenBC, et al. (2012) Large-scale discovery of enhancers from human heart tissue. Nat Genet 44 : 89–93.

18. ViselA, MinovitskyS, DubchakI, PennacchioLA (2007) VISTA Enhancer Browser–a database of tissue-specific human enhancers. Nucleic acids research 35: D88–92.

19. das NevesL, DuchalaCS, Tolentino-SilvaF, HaxhiuMA, ColmenaresC, et al. (1999) Disruption of the murine nuclear factor I-A gene (Nfia) results in perinatal lethality, hydrocephalus, and agenesis of the corpus callosum. Proceedings of the National Academy of Sciences of the United States of America 96 : 11946–11951.

20. Steele-PerkinsG, PlachezC, ButzKG, YangG, BachurskiCJ, et al. (2005) The transcription factor gene Nfib is essential for both lung maturation and brain development. Molecular and cellular biology 25 : 685–698.

21. ZhangD, ZeldinDC, BlackshearPJ (2007) Regulatory factor X4 variant 3: a transcription factor involved in brain development and disease. Journal of neuroscience research 85 : 3515–3522.

22. GronostajskiRM (1987) Site-specific DNA binding of nuclear factor I: effect of the spacer region. Nucleic acids research 15 : 5545–5559.

23. PennacchioLA, AhituvN, MosesAM, PrabhakarS, NobregaMA, et al. (2006) In vivo enhancer analysis of human conserved non-coding sequences. Nature 444 : 499–502.

24. LiQ, RitterD, YangN, DongZ, LiH, et al. (2010) A systematic approach to identify functional motifs within vertebrate developmental enhancers. Dev Biol 337 : 484–495.

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

26. ClarkeSL, VanderMeerJE, WengerAM, SchaarBT, AhituvN, et al. (2012) Human developmental enhancers conserved between deuterostomes and protostomes. PLoS Genet 8: e1002852.

27. BrittenRJ, DavidsonEH (1971) Repetitive and non-repetitive DNA sequences and a speculation on the origins of evolutionary novelty. The Quarterly review of biology 46 : 111–138.

28. BejeranoG, LoweCB, AhituvN, KingB, SiepelA, et al. (2006) A distal enhancer and an ultraconserved exon are derived from a novel retroposon. Nature 441 : 87–90.

29. SasakiT, NishiharaH, HirakawaM, FujimuraK, TanakaM, et al. (2008) Possible involvement of SINEs in mammalian-specific brain formation. Proceedings of the National Academy of Sciences of the United States of America 105 : 4220–4225.

30. LoweCB, BejeranoG, HausslerD (2007) Thousands of human mobile element fragments undergo strong purifying selection near developmental genes. Proceedings of the National Academy of Sciences of the United States of America 104 : 8005–8010.

31. HanW, KwanKY, ShimS, LamMM, ShinY, et al. (2011) TBR1 directly represses Fezf2 to control the laminar origin and development of the corticospinal tract. Proc Natl Acad Sci U S A 108 : 3041–3046.

32. McKennaWL, BetancourtJ, LarkinKA, AbramsB, GuoC, et al. (2011) Tbr1 and Fezf2 regulate alternate corticofugal neuronal identities during neocortical development. J Neurosci 31 : 549–564.

33. TashiroK, TeissierA, KobayashiN, NakanishiA, SasakiT, et al. (2011) A mammalian conserved element derived from SINE displays enhancer properties recapitulating Satb2 expression in early-born callosal projection neurons. PloS one 6: e28497.

34. OvcharenkoI, LootsGG, NobregaMA, HardisonRC, MillerW, et al. (2005) Evolution and functional classification of vertebrate gene deserts. Genome Res 15 : 137–145.

35. FrankelN, DavisGK, VargasD, WangS, PayreF, et al. (2010) Phenotypic robustness conferred by apparently redundant transcriptional enhancers. Nature 466 : 490–493.

36. PerryMW, BoettigerAN, BothmaJP, LevineM (2010) Shadow enhancers foster robustness of Drosophila gastrulation. Current biology : CB 20 : 1562–1567.

37. SpitzF, FurlongEE (2012) Transcription factors: from enhancer binding to developmental control. Nat Rev Genet 13 : 613–626.

38. SrinivasanK, LeoneDP, BatesonRK, DobrevaG, KohwiY, et al. (2012) A network of genetic repression and derepression specifies projection fates in the developing neocortex. Proc Natl Acad Sci U S A 109 : 19071–19078.

39. OkadaN, SasakiT, ShimogoriT, NishiharaH (2010) Emergence of mammals by emergency: exaptation. Genes Cells 15 : 801–812.

40. KamalM, XieX, LanderES (2006) A large family of ancient repeat elements in the human genome is under strong selection. Proc Natl Acad Sci U S A 103 : 2740–2745.

41. JacquesPE, JeyakaniJ, BourqueG (2013) The majority of primate-specific regulatory sequences are derived from transposable elements. PLoS Genet 9: e1003504.

42. BedogniF, HodgeRD, ElsenGE, NelsonBR, DazaRA, et al. (2010) Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex. Proceedings of the National Academy of Sciences of the United States of America 107 : 13129–13134.

43. JoshiPS, MolyneauxBJ, FengL, XieX, MacklisJD, et al. (2008) Bhlhb5 regulates the postmitotic acquisition of area identities in layers II–V of the developing neocortex. Neuron 60 : 258–272.

44. Science AIfB (2009) Allen Developing Mouse Brain Atlas.

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

46. HsuF, KentWJ, ClawsonH, KuhnRM, DiekhansM, et al. (2006) The UCSC Known Genes. Bioinformatics 22 : 1036–1046.

47. HalperinY, LinhartC, UlitskyI, ShamirR (2009) Allegro: analyzing expression and sequence in concert to discover regulatory programs. Nucleic Acids Res 37 : 1566–1579.

48. RothFP, HughesJD, EstepPW, ChurchGM (1998) Finding DNA regulatory motifs within unaligned noncoding sequences clustered by whole-genome mRNA quantitation. Nat Biotechnol 16 : 939–945.

49. LiuX, BrutlagDL, LiuJS (2001) BioProspector: discovering conserved DNA motifs in upstream regulatory regions of co-expressed genes. Pac Symp Biocomput 127–138.

50. SharovAA, KoMS (2009) Exhaustive search for over-represented DNA sequence motifs with CisFinder. DNA Res 16 : 261–273.

51. LiuXS, BrutlagDL, LiuJS (2002) An algorithm for finding protein-DNA binding sites with applications to chromatin-immunoprecipitation microarray experiments. Nat Biotechnol 20 : 835–839.

52. BaileyTL, ElkanC (1994) Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Proc Int Conf Intell Syst Mol Biol 2 : 28–36.

53. ValenE, SandelinA, WintherO, KroghA (2009) Discovery of regulatory elements is improved by a discriminatory approach. PLoS Comput Biol 5: e1000562.

54. ThijsG, MarchalK, LescotM, RombautsS, De MoorB, et al. (2002) A Gibbs sampling method to detect overrepresented motifs in the upstream regions of coexpressed genes. J Comput Biol 9 : 447–464.

55. DogruelM, DownTA, HubbardTJ (2008) NestedMICA as an ab initio protein motif discovery tool. BMC Bioinformatics 9 : 19.

56. PavesiG, MauriG, PesoleG (2001) An algorithm for finding signals of unknown length in DNA sequences. Bioinformatics 17 Suppl 1: S207–214.

57. WengerAM, ClarkeSL, GuturuH, ChenJ, SchaarBT, et al. (2013) PRISM offers a comprehensive genomic approach to transcription factor function prediction. Genome Res 23 : 889–904.

58. KelAE, GosslingE, ReuterI, CheremushkinE, Kel-MargoulisOV, et al. (2003) MATCH: A tool for searching transcription factor binding sites in DNA sequences. Nucleic Acids Res 31 : 3576–3579.

59. SiepelA, BejeranoG, PedersenJS, HinrichsAS, HouM, et al. (2005) Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res 15 : 1034–1050.

60. KentWJ, BaertschR, HinrichsA, MillerW, HausslerD (2003) Evolution's cauldron: duplication, deletion, and rearrangement in the mouse and human genomes. Proc Natl Acad Sci U S A 100 : 11484–11489.

61. BaileyJA, GuZ, ClarkRA, ReinertK, SamonteRV, et al. (2002) Recent segmental duplications in the human genome. Science 297 : 1003–1007.

62. PersampieriJ, RitterDI, LeesD, LehoczkyJ, LiQ, et al. (2008) cneViewer: a database of conserved non-coding elements for studies of tissue-specific gene regulation. Bioinformatics 24 : 2418–2419.

63. Meester-SmoorMA, JanssenMJ, GrosveldGC, de KleinA, vanIWF, et al. (2008) MN1 affects expression of genes involved in hematopoiesis and can enhance as well as inhibit RAR/RXR-induced gene expression. Carcinogenesis 29 : 2025–2034.

64. PiperM, MoldrichRX, LindwallC, LittleE, BarryG, et al. (2009) Multiple non-cell-autonomous defects underlie neocortical callosal dysgenesis in Nfib-deficient mice. Neural Dev 4 : 43.

65. KovachC, DixitR, LiS, MattarP, WilkinsonG, et al. (2012) Neurog2 Simultaneously Activates and Represses Alternative Gene Expression Programs in the Developing Neocortex. Cereb Cortex 23 (8) 1884–900.