#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Quantitative Models of the Mechanisms That Control Genome-Wide Patterns of Transcription Factor Binding during Early Development


Transcription factors that drive complex patterns of gene expression during animal development bind to thousands of genomic regions, with quantitative differences in binding across bound regions mediating their activity. While we now have tools to characterize the DNA affinities of these proteins and to precisely measure their genome-wide distribution in vivo, our understanding of the forces that determine where, when, and to what extent they bind remains primitive. Here we use a thermodynamic model of transcription factor binding to evaluate the contribution of different biophysical forces to the binding of five regulators of early embryonic anterior-posterior patterning in Drosophila melanogaster. Predictions based on DNA sequence and in vitro protein-DNA affinities alone achieve a correlation of ∼0.4 with experimental measurements of in vivo binding. Incorporating cooperativity and competition among the five factors, and accounting for spatial patterning by modeling binding in every nucleus independently, had little effect on prediction accuracy. A major source of error was the prediction of binding events that do not occur in vivo, which we hypothesized reflected reduced accessibility of chromatin. To test this, we incorporated experimental measurements of genome-wide DNA accessibility into our model, effectively restricting predicted binding to regions of open chromatin. This dramatically improved our predictions to a correlation of 0.6–0.9 for various factors across known target genes. Finally, we used our model to quantify the roles of DNA sequence, accessibility, and binding competition and cooperativity. Our results show that, in regions of open chromatin, binding can be predicted almost exclusively by the sequence specificity of individual factors, with a minimal role for protein interactions. We suggest that a combination of experimentally determined chromatin accessibility data and simple computational models of transcription factor binding may be used to predict the binding landscape of any animal transcription factor with significant precision.


Vyšlo v časopise: Quantitative Models of the Mechanisms That Control Genome-Wide Patterns of Transcription Factor Binding during Early Development. PLoS Genet 7(2): e32767. doi:10.1371/journal.pgen.1001290
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001290

Souhrn

Transcription factors that drive complex patterns of gene expression during animal development bind to thousands of genomic regions, with quantitative differences in binding across bound regions mediating their activity. While we now have tools to characterize the DNA affinities of these proteins and to precisely measure their genome-wide distribution in vivo, our understanding of the forces that determine where, when, and to what extent they bind remains primitive. Here we use a thermodynamic model of transcription factor binding to evaluate the contribution of different biophysical forces to the binding of five regulators of early embryonic anterior-posterior patterning in Drosophila melanogaster. Predictions based on DNA sequence and in vitro protein-DNA affinities alone achieve a correlation of ∼0.4 with experimental measurements of in vivo binding. Incorporating cooperativity and competition among the five factors, and accounting for spatial patterning by modeling binding in every nucleus independently, had little effect on prediction accuracy. A major source of error was the prediction of binding events that do not occur in vivo, which we hypothesized reflected reduced accessibility of chromatin. To test this, we incorporated experimental measurements of genome-wide DNA accessibility into our model, effectively restricting predicted binding to regions of open chromatin. This dramatically improved our predictions to a correlation of 0.6–0.9 for various factors across known target genes. Finally, we used our model to quantify the roles of DNA sequence, accessibility, and binding competition and cooperativity. Our results show that, in regions of open chromatin, binding can be predicted almost exclusively by the sequence specificity of individual factors, with a minimal role for protein interactions. We suggest that a combination of experimentally determined chromatin accessibility data and simple computational models of transcription factor binding may be used to predict the binding landscape of any animal transcription factor with significant precision.


Zdroje

1. WalterJ

DeverCA

BigginMD

1994 Two homeo domain proteins bind with similar specificity to a wide range of DNA sites in Drosophila embryos. Genes Dev 8 1678 1692

2. CarrA

BigginMD

1999 A comparison of in vivo and in vitro DNA-binding specificities suggests a new model for homeoprotein DNA binding in Drosophila embryos. EMBO Journal 18 1598 1608

3. BoyerLA

LeeTI

ColeMF

JohnstoneSE

LevineSS

2005 Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122 947 956

4. BiedaM

XuX

SingerMA

GreenR

FarnhamPJ

2006 Unbiased location analysis of E2F1-binding sites suggests a widespread role for E2F1 in the human genome. Genome Res 16 595 605

5. YangA

ZhuZ

KapranovP

McKeonF

ChurchGM

2006 Relationships between p63 binding, DNA sequence, transcription activity, and biological function in human cells. Mol Cell 24 593 602

6. SandmannT

GirardotC

BrehmeM

TongprasitW

StolcV

2007 A core transcriptional network for early mesoderm development in Drosophila melanogaster. Genes Dev 21 436 449

7. ZeitlingerJ

ZinzenRP

StarkA

KellisM

ZhangH

2007 Whole-genome ChIP-chip analysis of Dorsal, Twist, and Snail suggests integration of diverse patterning processes in the Drosophila embryo. Genes Dev 21 385 390

8. JohnsonDS

MortazaviA

MyersRM

WoldB

2007 Genome-wide mapping of in vivo protein-DNA interactions. Science 316 1497 1502

9. RobertsonG

HirstM

BainbridgeM

BilenkyM

ZhaoY

2007 Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat Methods 4 651 657

10. ChenX

XuH

YuanP

FangF

HussM

2008 Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133 1106 1117

11. ConsortiumTEP

2007 Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447 799 816

12. GeorletteD

AhnS

MacAlpineDM

CheungE

LewisPW

2007 Genomic profiling and expression studies reveal both positive and negative activities for the Drosophila Myb MuvB/dREAM complex in proliferating cells. Genes Dev 21 2880 2896

13. LiX-Y

MacarthurS

BourgonR

NixD

PollardDA

2008 Transcription Factors Bind Thousands of Active and Inactive Regions in the Drosophila Blastoderm. PLoS Biol 6 e27 doi:10.1371/journal.pbio.0060027

14. FullwoodMJ

LiuMH

PanYF

LiuJ

XuH

2009 An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 462 58 64

15. BojSF

ServitjaJM

MartinD

RiosM

TalianidisI

2009 Functional targets of the monogenic diabetes transcription factors HNF-1alpha and HNF-4alpha are highly conserved between mice and humans. Diabetes 58 1245 1253

16. MacarthurS

LiX-Y

LiJ

BrownJB

ChuHC

2009 Developmental roles of 21 Drosophila transcription factors are determined by quantitative differences in binding to an overlapping set of thousands of genomic regions. Genome Biol 10 R80

17. CaoY

YaoZ

SarkarD

LawrenceM

SanchezGJ

2010 Genome-wide MyoD binding in skeletal muscle cells: a potential for broad cellular reprogramming. Dev Cell 18 662 674

18. BradleyRK

LiX-Y

TrapnellC

DavidsonS

PachterL

2010 Binding site turnover produces pervasive quantitative changes in transcription factor binding between closely related Drosophila species. PLoS Biol 8 e1000343 doi:10.1371/journal.pbio.1000343

19. LiangZ

BigginMD

1998 Eve and ftz regulate a wide array of genes in blastoderm embryos: the selector homeoproteins directly or indirectly regulate most genes in Drosophila. Development 125 4471 4482

20. MoormanC

SunLV

WangJ

de WitE

TalhoutW

2006 Hotspots of transcription factor colocalization in the genome of Drosophila melanogaster. Proc Natl Acad Sci U S A 103 12027 12032

21. OuyangZ

ZhouQ

WongWH

2009 ChIP-Seq of transcription factors predicts absolute and differential gene expression in embryonic stem cells. Proc Natl Acad Sci U S A 106 21521 21526

22. ZinzenRP

GirardotC

GagneurJ

BraunM

FurlongEEM

2009 Combinatorial binding predicts spatio-temporal cis-regulatory activity. Nature 461 65 70

23. WunderlichZ

MirnyLA

2009 Different gene regulation strategies revealed by analysis of binding motifs. Trends Genet 25 434 440

24. IyerVR

HorakCE

ScafeCS

BotsteinD

SnyderM

2001 Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF. Nature 409 533 538

25. LiuX

LeeCK

GranekJA

ClarkeND

LiebJD

2006 Whole-genome comparison of Leu3 binding in vitro and in vivo reveals the importance of nucleosome occupancy in target site selection. Genome Res 16 1517 1528

26. StanojevicD

SmallS

LevineM

1991 Regulation of a segmentation stripe by overlapping activators and repressors in the Drosophila embryo. Science (New York, NY) 254 1385 1387

27. MakeevVJ

LifanovAP

NazinaAG

PapatsenkoDA

2003 Distance preferences in the arrangement of binding motifs and hierarchical levels in organization of transcription regulatory information. Nucleic Acids Research 31 6016 6026

28. WolffeAP

1994 Nucleosome positioning and modification: chromatin structures that potentiate transcription. Trends Biochem Sci 19 240 244

29. CosmaMP

TanakaT

NasmythK

1999 Ordered recruitment of transcription and chromatin remodeling factors to a cell cycle- and developmentally regulated promoter. Cell 97 299 311

30. AgaliotiT

LomvardasS

ParekhB

YieJ

ManiatisT

2000 Ordered recruitment of chromatin modifying and general transcription factors to the IFN-beta promoter. Cell 103 667 678

31. CarrA

BigginMD

2000 Accessibility of transcriptionally inactive genes is specifically reduced at homeoprotein-DNA binding sites in Drosophila. Nucleic Acids Res 28 2839 2846

32. NarlikarGJ

FanH-Y

KingstonRE

2002 Cooperation between complexes that regulate chromatin structure and transcription. Cell 108 475 487

33. MorseRH

2007 Transcription factor access to promoter elements. J Cell Biochem 102 560 570

34. TaylorIC

WorkmanJL

SchuetzTJ

KingstonRE

1991 Facilitated binding of GAL4 and heat shock factor to nucleosomal templates: differential function of DNA-binding domains. Genes Dev 5 1285 1298

35. AdamsCC

WorkmanJL

1995 Binding of disparate transcriptional activators to nucleosomal DNA is inherently cooperative. Mol Cell Biol 15 1405 1421

36. JohnsonAD

1995 Molecular mechanisms of cell-type determination in budding yeast. Curr Opin Genet Dev 5 552 558

37. VasheeS

MelcherK

DingWV

JohnstonSA

KodadekT

1998 Evidence for two modes of cooperative DNA binding in vivo that do not involve direct protein-protein interactions. Curr Biol 8 452 458

38. BolouriH

DavidsonEH

2003 Transcriptional regulatory cascades in development: initial rates, not steady state, determine network kinetics. Proc Natl Acad Sci U S A 100 9371 9376

39. MillerJA

WidomJ

2003 Collaborative competition mechanism for gene activation in vivo. Mol Cell Biol 23 1623 1632

40. ZeitlingerJ

SimonI

HarbisonCT

HannettNM

VolkertTL

2003 Program-specific distribution of a transcription factor dependent on partner transcription factor and MAPK signaling. Cell 113 395 404

41. BuckMJ

LiebJD

2006 A chromatin-mediated mechanism for specification of conditional transcription factor targets. Nat Genet 38 1446 1451

42. MannRS

LelliKM

JoshiR

2009 Hox specificity unique roles for cofactors and collaborators. Curr Top Dev Biol 88 63 101

43. Campos-OrtegaJA

HartensteinV

1997 The Embryonic Development of Drosophila melanogaster. Berlin Springer-Verlag

44. Nusslein-VolhardC

WieschausE

1980 Mutations affecting segment number and polarity in Drosophila. Nature 287 795 801

45. St JohnstonD

Nusslein-VolhardC

1992 The origin of pattern and polarity in the Drosophila embryo. Cell 68 201 219

46. Rivera-PomarR

JäckleH

1996 From gradients to stripes in Drosophila embryogenesis: filling in the gaps. Trends Genet 12 478 483

47. FowlkesCC

HendriksCLL

KeränenSVE

WeberGH

RübelO

2008 A quantitative spatiotemporal atlas of gene expression in the Drosophila blastoderm. Cell 133 364 374

48. StormoGD

2000 DNA binding sites: representation and discovery. Bioinformatics 16 16 23

49. FrithMC

HansenU

WengZ

2001 Detection of cis-element clusters in higher eukaryotic DNA. Bioinformatics 17 878 889

50. RajewskyN

VergassolaM

GaulU

SiggiaED

2002 Computational detection of genomic cis-regulatory modules applied to body patterning in the early Drosophila embryo. BMC Bioinformatics 3 30

51. BarashY

ElidanG

FriedmanN

KaplanT

2003 Modeling dependencies in protein-DNA binding sites. Proceedings of the seventh annual international conference on Research in computational molecular biology Berlin, Germany ACM 28 37

52. BulykML

2003 Computational prediction of transcription-factor binding site locations. Genome Biol 5 201

53. SinhaS

van NimwegenE

SiggiaED

2003 A probabilistic method to detect regulatory modules. Bioinformatics 19 Suppl 1 i292 301

54. BarashY

ElidanG

KaplanT

FriedmanN

2005 CIS: compound importance sampling method for protein-DNA binding site p-value estimation. Bioinformatics 21 596 600

55. GranekJA

ClarkeND

2005 Explicit equilibrium modeling of transcription-factor binding and gene regulation. Genome Biol 6 R87

56. SinhaS

2006 On counting position weight matrix matches in a sequence, with application to discriminative motif finding. Bioinformatics 22 e454 463

57. NarlikarL

GordanR

HarteminkAJ

2007 A nucleosome-guided map of transcription factor binding sites in yeast. PLoS Comput Biol 3 e215 doi:10.1371/journal.pcbi.0030215

58. RoiderHG

KanhereA

MankeT

VingronM

2007 Predicting transcription factor affinities to DNA from a biophysical model. Bioinformatics 23 134 141

59. WardLD

BussemakerHJ

2008 Predicting functional transcription factor binding through alignment-free and affinity-based analysis of orthologous promoter sequences. Bioinformatics 24 i165 171

60. HeX

ChenCC

HongF

FangF

SinhaS

2009 A biophysical model for analysis of transcription factor interaction and binding site arrangement from genome-wide binding data. PLoS ONE 4 e8155 doi:10.1371/journal.pone.0008155

61. NarlikarL

OvcharenkoI

2009 Identifying regulatory elements in eukaryotic genomes. Brief Funct Genomic Proteomic 8 215 230

62. WassonT

HarteminkAJ

2009 An ensemble model of competitive multi-factor binding of the genome. Genome Res 19 2101 2112

63. WhitingtonT

PerkinsAC

BaileyTL

2009 High-throughput chromatin information enables accurate tissue-specific prediction of transcription factor binding sites. Nucleic Acids Research 37 14 25

64. WonKJ

AgarwalS

ShenL

ShoemakerR

RenB

2009 An integrated approach to identifying cis-regulatory modules in the human genome. PLoS ONE 4 e5501 doi:10.1371/journal.pone.0005501

65. ErnstJ

PlastererHL

SimonI

Bar-JosephZ

2010 Integrating multiple evidence sources to predict transcription factor binding in the human genome. Genome Res 20 526 536

66. HeX

SameeMA

BlattiC

SinhaS

2010 Thermodynamics-based models of transcriptional regulation by enhancers: the roles of synergistic activation, cooperative binding and short-range repression. PLoS Comput Biol 6 e1000935 doi:10.1371/journal.pcbi.1000935

67. RamseySA

KnijnenburgTA

KennedyKA

ZakDE

GilchristM

2010 Genome-wide histone acetylation data improve prediction of mammalian transcription factor binding sites. Bioinformatics 26 2071 2075

68. WonK-J

RenB

WangW

2010 Genome-wide prediction of transcription factor binding sites using an integrated model. Genome Biol 11 R7

69. SegalE

Raveh-SadkaT

SchroederM

UnnerstallU

GaulU

2008 Predicting expression patterns from regulatory sequence in Drosophila segmentation. Nature 451 535 540

70. Raveh-SadkaT

LevoM

SegalE

2009 Incorporating nucleosomes into thermodynamic models of transcription regulation. Genome Res 19 1480 1496

71. KazemianM

BlattiC

RichardsA

McCutchanM

Wakabayashi-ItoN

2010 Quantitative analysis of the Drosophila segmentation regulatory network using pattern generating potentials. PLoS Biol 8 e1000456 doi:10.1371/journal.pbio.1000456

72. LinS

RiggsAD

1975 The general affinity of lac repressor for E. coli DNA: implications for gene regulation in procaryotes and eucaryotes. Cell 4 107 111

73. von HippelPH

RevzinA

GrossCA

WangAC

1974 Nonspecific DNA binding of genome regulating proteins as a biological control mechanism: 1. The lac operon: Equilibrium aspects. Proc Natl Acad Sci USA 71 4808 4812

74. KulpD

HausslerD

ReeseMG

EeckmanFH

1996 A generalized hidden Markov model for the recognition of human genes in DNA. Proc Int Conf Intell Syst Mol Biol 4 134 142

75. RabinerL

1989 A Tutorial on Hidden Markov Moldes and Selected Applications in Speech Recognition. P Ieee 77 257 286

76. AckersGK

JohnsonAD

SheaMA

1982 Quantitative model for gene regulation by lambda phage repressor. Proc Natl Acad Sci USA 79 1129 1133

77. BuchlerNE

GerlandU

HwaT

2003 On schemes of combinatorial transcription logic. Proc Natl Acad Sci USA 100 5136 5141

78. SchroederMD

PearceM

FakJ

FanH

UnnerstallU

2004 Transcriptional control in the segmentation gene network of Drosophila. PLoS Biol 2 e271 doi:10.1371/journal.pbio.0020271

79. BintuL

BuchlerNE

GarciaHG

GerlandU

HwaT

2005 Transcriptional regulation by the numbers: models. Current Opinion in Genetics & Development 15 116 124

80. GertzJ

CohenBA

2009 Environment-specific combinatorial cis-regulation in synthetic promoters. Mol Syst Biol 5 1 9

81. TothJ

BigginMD

2000 The specificity of protein-DNA crosslinking by formaldehyde: in vitro and in drosophila embryos. Nucleic Acids Res 28 e4

82. AuerbachRK

EuskirchenG

RozowskyJ

Lamarre-VincentN

MoqtaderiZ

2009 Mapping accessible chromatin regions using Sono-Seq. Proc Natl Acad Sci USA 106 14926 14931

83. CapaldiA

KaplanT

LiuY

HabibN

RegevA

2008 Structure and function of a transcriptional network activated by the MAPK Hog1. Nat Genet 40 1300 1306

84. BrodyT

1999 The Interactive Fly: gene networks, development and the Internet. Trends Genet 15 333 334

85. HareEE

PetersonBK

IyerVN

MeierR

EisenMB

2008 Sepsid even-skipped enhancers are functionally conserved in Drosophila despite lack of sequence conservation. PLoS Genet 4 e1000106 doi:10.1371/journal.pgen.1000106

86. KimJ

HeX

SinhaS

2009 Evolution of regulatory sequences in 12 Drosophila species. PLoS Genet 5 e1000330 doi:10.1371/journal.pgen.1000330

87. PolachKJ

WidomJ

1996 A model for the cooperative binding of eukaryotic regulatory proteins to nucleosomal target sites. J Mol Biol 258 800 812

88. MirnyL

2009 Nucleosome-mediated cooperativity between transcription factors. Arxiv preprint arXiv 09012905

89. GrossDS

GarrardWT

1988 Nuclease hypersensitive sites in chromatin. Annu Rev Biochem 57 159 197

90. HesselberthJR

ChenX

ZhangZ

SaboPJ

SandstromR

2009 Global mapping of protein-DNA interactions in vivo by digital genomic footprinting. Nat Meth 6 283 289

91. SaboPJ

KuehnMS

ThurmanR

JohnsonBE

JohnsonEM

2006 Genome-scale mapping of DNase I sensitivity in vivo using tiling DNA microarrays. Nat Meth 3 511 518

92. ZhangY

MoqtaderiZ

RattnerBP

EuskirchenG

SnyderM

2009 Intrinsic histone-DNA interactions are not the major determinant of nucleosome positions in vivo. Nat Struct Mol Biol 16 847 852

93. SegalE

Fondufe-MittendorfY

ChenL

ThåströmA

FieldY

2006 A genomic code for nucleosome positioning. Nature 442 772 778

94. SmallS

BlairA

LevineM

1992 Regulation of even-skipped stripe 2 in the Drosophila embryo. EMBO J 11 4047 4057

95. ArnostiDN

BaroloS

LevineM

SmallS

1996 The eve stripe 2 enhancer employs multiple modes of transcriptional synergy. Development 122 205 214

96. KulkarniMM

ArnostiDN

2005 cis-regulatory logic of short-range transcriptional repression in Drosophila melanogaster. Molecular and Cellular Biology 25 3411 3420

97. FakhouriWD

AyA

SayalR

DreschJ

DayringerE

2010 Deciphering a transcriptional regulatory code: modeling short-range repression in the Drosophila embryo. Molecular Systems Biology 6 1 14

98. HammersleyJM

HandscombDC

1964 Monte Carlo methods. London, New York Methuen; Wiley vii, 178

99. SteihaugT

1983 The Conjugate Gradient Method and Trust Regions in Large Scale Optimization. SIAM Journal on Numerical Analysis 20 626 637

100. ColemanTF

LiY

1996 An Interior Trust Region Approach for Nonlinear Minimization Subject to Bounds. SIAM J Optim 6 418 445

101. ArbeitmanM

FurlongE

ImamF

JohnsonE

NullB

2002 Gene expression during the life cycle of Drosophila melanogaster. Science 297 2270 2275

102. AgiusP

ArveyA

ChangW

NobleWS

LeslieC

2010 High Resolution Models of Transcription Factor-DNA Affinities Improve In Vitro and In Vivo Binding Predictions. PLoS Comput Biol 6 e1000916 doi:10.1371/journal.pcbi.1000916

103. ZinzenRP

SengerK

LevineM

PapatsenkoD

2006 Computational models for neurogenic gene expression in the Drosophila embryo. Curr Biol 16 1358 1365

104. RouletE

BussoS

CamargoAA

SimpsonAJ

MermodN

2002 High-throughput SELEX SAGE method for quantitative modeling of transcription-factor binding sites. Nat Biotechnol 20 831 835

105. NoyesMB

MengX

WakabayashiA

SinhaS

BrodskyMH

2008 A systematic characterization of factors that regulate Drosophila segmentation via a bacterial one-hybrid system. Nucleic Acids Research 36 2547 2560

106. LangmeadB

TrapnellC

PopM

SalzbergSL

2009 Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10 R25

107. GoldbergD

HollandJ

1988 Genetic Algorithms and Machine Learning. Machine learning 3 95 99

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2011 Číslo 2
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#