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1 /W > ' d d d D W d d > d > d d : ' d d d d h d / D/d, d h d D ^ h Z /W >' D dd D D ddddd W edeedddedd : ' D dd D D ddddd W edeeedeeed < /W 1

2 d E /W D /W, d d E /W d /W E d K ddl edl ddl de / d /W W d ed ZK / d Z d& d d& E ZE 2

3 dddd / d& ' / E d ddde ^ ddde ^ t ddde, dddd d d d& D Y ddde ^ t ddde ddde ^ dddd D ^ ddde, dddd d& ddde Z ddde < ddde < K ^ ddde s ddde ' dddd D Y dddd s ddde ddde Z ddde s ddde D Y dddd K ddde < ddde < K ^ ddde ' dddd W Z dddd / : ddde d ddde s ddde s Z D ddde dddd d ' ddde K dddd > ddde d 3

4 /W ddde : ddde Z ddde /W Z W dddd d E d& E d d& d /W ddde : ddde Z ddde E, dddd ' & ddde D ddde, ddde ^ /W < ddde s ddde ddde > ddde K d < ddde s ddde /W Z dddd d /W dddd ' dddd D W ddde t & dddd Z dddd > ddde ^ dddd K > ddde /W, 4

5 t & dddd K ' dddd dddd ' dddd dddd / Z / > Z/> Z/> /W & dddd K /W d ^ E d Z/> > ddde /W Z/> /W t E d /W t de dddd Z > ddde /W & d / 5

6 /W d d& /W & d t /W & d / d & d D> W d d > ddde t & dddd K D d K d K d D D> Z/> ^ d ^d Z/> / D d e d t t d 6

7 /W /W Z/> /W K & d d ^ /W D /W D / d Z/> & Z/> /W D d d /W & d < ddde s ddde & d & d d d d d & d 7

8 /W d E ^ d E / E d& & d & d & d d > s W λ ^ D ( x) 1 e λ V F(x) = 1 e λ d d s /W ^e d E / d& E & ^d D s ' ^d ' n β d β n d& 8

9 ^ D d Z/> t & d & d E d / & d d d d & d d & d, t / E dddd d de de D d& Z d /W Z D ' dddd t s ddde ddde t & dddd & dddd / & d d K 'D ' dddd & d Z/> 'D t 9

10 md ddd Y ^d W Z D^ md dd 'D 'D dd t 'D e dd dd ''' dd ' dd dd ed d 'D dd de 'D, 'D Z/> W^^D 'D / Z/> Z/> / / & d Z/> ddl edl / & d Z/> d d / K /W D D / & d d d D 10

11 & d K d ^d D ^e D ^e & d t / D h D ^dd ^dd d K K D d& Z dddd d D & ^d d ZK d ed & d & ^d ^e d& d& Z^d 'W ^ & ^dd ^dd 11

12 , K /W t & dddd t D /W ' dddd d, & ^e ^e d& Dy Z^d ^Z& Z dddd t d& 'W d& ' ' dddd d & ^dd ^de K /W /W : ddde s ddde D Y dddd / & Z dddd s ddde / Z/> /W Z/> D d Z/> d d D /W 12

13 / /W D ' dddd & K dd d d dd d ddl deed dded K ddl d d demd ed mdd d d ddmd ed & ^d & d edmd ed mdd d d d ' ddde W deee ^ deed dddd d ddde ' ddde ^ dddd Z d& t > ddde /W K dddd < K ^ ddde ^ t ddde ' dddd K /W & dddd d /W d 13

14 /W / /W & d & d K d > ddde t & dddd d de de D d& Z dddd d K /W d& ' dddd Z/> & ^dd ^de E & d & d& Z d d& W Z dddd d /W Z/> 14

15 ' t Z/> D ' dddd, EK EK > dddd s E < dddd d,kd Z dddd D d& Z/> d& / d& d& K E ^ D d /W d /W E Z W dddd E d d d& K dddd ddde < K ^ ddde ^ ddde > ddde, dddd d K dddd z dddd / 15

16 d& KZd KZd KZd K dddd t /W d / /W K t & /W D ^ t /W D d θ θ / ' θ n β ^d & 16

17 E[C fw (x; M, L,θ)] = b(x)+ E[C rv (x;m, L,θ)] = b(x)+ L i i L m i f fw ((x l i );θ) m i f rv ((x l i ));θ) d d d > t d θ l θ l θ t d ld ld d ld d ld d E[C fw (x; M, L,θ)] = b(x)+ d L m i f ((x l i );θ) + m i,i+1 f fw ((x (l i,i+1 d i,i+1 2 );θ) I(d i,i+1 < d * ) i L 1 E[C rv (x;m, L,θ)] = b(x)+ L i m i f ( (x l i );θ) + m i,i+1 f rv ((x (l i,i+1 + d i,i+1 2 ));θ) I(d < i,i+1 d* ) i L 1 i E > m ld d / ^ d ^ d & d ld ld dl ld l ld dl ld d 17

18 d /W & d d argmax L,M,θ P(L, M,θ C) = argmax L,M,θ P(C L, M,θ) P(L, M,θ) d t d d W > D θ d W > D θ & α > θ α > θ & obj r (L, M,θ) = α r (L,θ)+ (C fw (x) E[C fw (x; M, L,θ)]) 2 + (C rv (x) E[C rv (x; M, L,θ)]) 2 d x r obj(l, M,θ) = obj r (L, M,θ) e r R Z / & de de d d D> (L (i+1), M (i+1) ) = argmin L,M obj(l, M,θ (i) ) e W (θ (i+1) ) = argmin θ obj(l (i+1), M (i+1),θ) e 18

19 d D> W d e Dd> e d Dd> & Dd> ^ D d e, D> / h de d & ^dd d & / & ^dd & D> d α > θ d / /W h /W t e d 19

20 D D W^^D DD ddde d &^d ddd dd D t &/DK ddde W^^D d > d / d d d / D> W e e d mdd d d de & ^dd D> / mdd d d d α > θ d / ^ D / d t α > θ lα d > < > 20

21 < t d < K(r) = x in r 1 2 (C 2 fw(x)+crv(x)) 2 d α d d d K α d ld dd t α d ld d dd d m mdd d d dd d d mdd d : ddde s ddde K e & /W /W & dd d d < K ^ ddde ' ddde 21

22 d D = n (log(obj null ) log(obj alternative )) e d d d ^ ^ D ^ d dd d d & ^d d /W d d & ^d d 22

23 d d & ^d d W d ^ d & ^d d d t & ^d d & ^d d & ^d d ^d dd d W K / ddd ddd K ^ ddd ddd & d& 'W 'D d Dy Z^d ^Z& Z Z dddd 23

24 W Z/> ^ /W D D ' dddd d /W D d& Z de e de e t dd d dd d d D < & d dd d dd d, /W Z Z dddd 'W d& ddde s ddde ' dddd ^ d d ' : / ' t, z d : d & E / / E 24

25 /,,, ^ E,,^Ededdddedddde d Z & & &tk > ' : ' > ' d > : ' D W d D W > /W > : ' d 25

26 & > & d / d /W / / d & D> W & D> & d d ' /W K D K /W & d d /W / E d E d& d d D d E d d Z K d d d d 26

27 d & d Z/> d /W Z/> Z/> Z/> d d / Z/> dd de dddd d d d d Z/> l ddd & Z/> Z/> Z/> dddl K ZK & d d d E Z /W D Z < d & d d /W K e dddd d & ^d ^d d ^d D d 27

28 D d / d d d d / & ^d ^e d 28

29 d d d K d Z/> d & h Z/> Z/> Z/> Z/> /W Z/> Z/> /W & Z/> Z/> ddd ^ ddd ddd h ZK ZK Method True positives False positves 1 Missing sites False positives filtered out AUC ROC BRACIL-db BRACIL-sb p-value p-value BRACIL-co peak callers (best) Peak callers (combined) We assume the total number of negatives to be 42, which is the number of motifs detected with p-value that does not match a reference binding site. Notice that, although not directly related, this value is also used to estimate the false positives for the peak callers. 29

30 Z Bailey TL, Boden M, Buske FA, Frith M, Grant CE, Clementi L, Ren J, Li WW, Noble WS MEME SUITE: tools for motif discovery and searching. Nucleic acids research 37: W Barski A, Cuddapah S, Cui K, Roh T-Y, Schones D, Wang Z, Wei G, Chepelev I, Zhao K High-Resolution Profiling of Histone Methylations in the Human Genome. Cell 129(4): Benson M, Pirrotta V The Drosophila zeste protein binds cooperatively to sites in many gene regulatory regions: implications for transvection and gene regulation. The EMBO journal 7: Berger MF, Bulyk ML Universal protein-binding microarrays for the comprehensive characterization of the DNA-binding specificities of transcription factors. Nature protocols 4: Berman BP, Nibu Y, Pfeiffer BD, Tomancak P, Celniker SE, Levine M, Rubin GM, Eisen MB Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome. Proceedings of the National Academy of Sciences of the United States of America 99: Boeva V, Surdez D, Guillon N, Tirode F, Fejes A, Delattre O, Barillot E De novo motif identification improves the accuracy of predicting transcription factor binding sites in ChIP-Seq data analysis. Nucleic Acids Research 38(11): e126-e126. Browning D, Busby S The regulation of bacterial transcription initiation. Nature Reviews Microbiology 2(1): Chauhan S, Sharma D, Singh A, Surolia A, Tyagi JS Comprehensive insights into Mycobacterium tuberculosis DevR (DosR) regulon activation switch. Nucleic acids research. Chauhan S, Tyagi JS Cooperative binding of phosphorylated DevR to upstream sites is necessary and sufficient for activation of the Rv3134c-devRS operon in Mycobacterium tuberculosis: implication in the induction of DevR target genes. Journal of bacteriology 190(12): Chen X, Xu H, Yuan P, Fang F, Huss M, Vega V, Wong E, Orlov Y, Zhang W, Jiang J et al Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133(6): Chung D, Park D, Myers K, Grass J, Kiley P, Landick R, Keleş S dpeak: high resolution identification of transcription factor binding sites from PET and SET ChIP-Seq data. PLoS computational biology 9: e Feng X, Grossman R, Stein L PeakRanger: a cloud-enabled peak caller for ChIP-seq data. BMC bioinformatics 12: 139. Furey TS ChIP-seq and beyond: new and improved methodologies to detect and characterize protein-dna interactions. Nature reviews Genetics 13: Galagan JE, Minch K, Peterson M, Lyubetskaya A, Azizi E, Sweet L, Gomes A, Rustad T, Dolganov G, Glotova I et al The Mycobacterium tuberculosis regulatory network and hypoxia. Nature. Gaszner M, Felsenfeld G Insulators: exploiting transcriptional and epigenetic mechanisms. Nature Reviews Genetics 7(9): Gertz J, Siggia E, Cohen B Analysis of combinatorial cis-regulation in synthetic and genomic promoters. Nature 457(7226): Giorgetti L, Siggers T, Tiana G, Caprara G, Notarbartolo S, Corona T, Pasparakis M, Milani P, Bulyk ML, Natoli G Noncooperative interactions between transcription factors and clustered DNA binding sites enable graded transcriptional responses to environmental inputs. Molecular cell 37: Gordon B, Li Y, Wang L, Sintsova A, van Bakel H, Tian S, Navarre W, Xia B, Liu J Lsr2 is a nucleoidassociated protein that targets AT-rich sequences and virulence genes in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences. Guo Y, Mahony S, Gifford DK High resolution genome wide binding event finding and motif discovery reveals transcription factor spatial binding constraints. PLoS computational biology 8: e Guo Y, Papachristoudis G, Altshuler RC, Gerber GK, Jaakkola TS, Gifford DK, Mahony S Discovering homotypic binding events at high spatial resolution. Bioinformatics (Oxford, England) 26: Hartman S, Bertone P, Nath A, Royce T, Gerstein M, Weissman S, Snyder M Global changes in STAT target 30

31 selection and transcription regulation upon interferon treatments. Genes & development 19(24): He X, Samee M, Blatti C, Sinha S Thermodynamics-Based Models of Transcriptional Regulation by Enhancers: The Roles of Synergistic Activation, Cooperative Binding and Short-Range Repression. PLoS Comput Biol 6(9): e Heintzman N, Stuart R, Hon G, Fu Y, Ching C, Hawkins D, Barrera L, Van Calcar S, Qu C, Ching K et al Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nature genetics 39(3): Johnson D, Mortazavi A, Myers R, Wold B Genome-wide mapping of in vivo protein-dna interactions. Science (New York, NY) 316(5830): Jothi R, Cuddapah S, Barski A, Cui K, Zhao K Genome-wide identification of in vivo protein-dna binding sites from ChIP-Seq data. Nucleic Acids Research 36(16): Kaplan N, Moore I, Fondufe-Mittendorf Y, Gossett A, Tillo D, Field Y, LeProust E, Hughes T, Lieb J, Widom J et al The DNA-encoded nucleosome organization of a eukaryotic genome. Nature 458(7236): Kharchenko P, Tolstorukov M, Park P Design and analysis of ChIP-seq experiments for DNA-binding proteins. Nature Biotechnology 26(12): Kim H, O'Shea E A quantitative model of transcription factor activated gene expression. Nature Structural & Molecular Biology 15(11): Landt SG, Marinov GK, Kundaje A, Kheradpour P, Pauli F, Batzoglou S, Bernstein BE, Bickel P, Brown JB, Cayting P et al ChIP-seq guidelines and practices of the ENCODE and modencode consortia. Genome research 22: Larochelle M, Drouin S, Robert F, Turcotte B Oxidative stress-activated zinc cluster protein Stb5 has dual activator/repressor functions required for pentose phosphate pathway regulation and NADPH production. Molecular and cellular biology 26: Lu T, Khalil A, Collins J Next-generation synthetic gene networks. Nat Biotechnol 27(12): Lun D, Sherrid A, Weiner B, Sherman D, Galagan J A blind deconvolution approach to high-resolution mapping of transcription factor binding sites from ChIP-seq data. Genome Biology 10(12): R142. MacQuarrie K, Fong A, Morse R, Tapscott S Genome-wide transcription factor binding: beyond direct target regulation. Trends in genetics : TIG 27(4): Maerkl S, Quake S A Systems Approach to Measuring the Binding Energy Landscapes of Transcription Factors. Science 315(5809): Mortazavi A, Thompson E, Garcia S, Myers R, Wold B Comparative genomics modeling of the NRSF/REST repressor network: From single conserved sites to genome-wide repertoire. Genome Research 16(10): Oppenheim AB, Kobiler O, Stavans J, Court DL, Adhya S Switches in bacteriophage lambda development. Annual review of genetics 39: Pepke S, Wold B, Mortazavi A Computation for ChIP-seq and RNA-seq studies. Nat Methods 6(11s): S22-S32. Pique-Regi R, Degner JF, Pai AA, Gaffney DJ, Gilad Y, Pritchard JK Accurate inference of transcription factor binding from DNA sequence and chromatin accessibility data. Genome research 21: Rhee H, Pugh F Comprehensive Genome-wide Protein-DNA Interactions Detected at Single-Nucleotide Resolution. Cell 147(6): Robertson G, Hirst M, Bainbridge M, Bilenky M, Zhao Y, Zeng T, Euskirchen G, Bernier B, Varhol R, Delaney A et al Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nature Methods 4(8): Roy S, Ernst J, Kharchenko PV, Kheradpour P, Negre N, Eaton ML, Landolin JM, Bristow CA, Ma L, Lin MF et al Identification of functional elements and regulatory circuits by Drosophila modencode. Science (New York, NY) 330: Rye M, Sætrom P, Drabløs F A manually curated ChIP-seq benchmark demonstrates room for improvement in current peak-finder programs. Nucleic Acids Research 39(4): e25-e25. Salmon-Divon M, Dvinge H, Tammoja K, Bertone P PeakAnalyzer: genome-wide annotation of chromatin binding and modification loci. BMC bioinformatics 11: 415. Schindler U, Baichwal VR Three NF-kappa B binding sites in the human E-selectin gene required for maximal tumor necrosis factor alpha-induced expression. Molecular and Cellular Biology 14: Segal E, Raveh-Sadka T, Schroeder M, Unnerstall U, Gaul U Predicting expression patterns from regulatory sequence in Drosophila segmentation. Nature 451(7178):

32 Segal E, Widom J From DNA sequence to transcriptional behaviour: a quantitative approach. Nature Reviews Genetics 10(7): Sharon E, Kalma Y, Sharp A, Raveh-Sadka T, Levo M, Zeevi D, Keren L, Yakhini Z, Weinberger A, Segal E Inferring gene regulatory logic from high-throughput measurements of thousands of systematically designed promoters. Nat Biotech 30(6): Stormo G, Zhao Y Determining the specificity of protein-dna interactions. Nature Reviews Genetics 11(11): Tanay A Extensive low-affinity transcriptional interactions in the yeast genome. Genome Research 16(8): Valouev A, Johnson D, Sundquist A, Medina C, Anton E, Batzoglou S, Myers R, Sidow A Genome-wide analysis of transcription factor binding sites based on ChIP-Seq data. Nature Methods 5(9): Van Nostrand EL, Kim SK Integrative analysis of C. elegans modencode ChIP-seq data sets to infer gene regulatory interactions. Genome research 23: Vasudeva-Rao H, McDonough K Expression of the Mycobacterium tuberculosis acr-coregulated Genes from the DevR (DosR) Regulon Is Controlled by Multiple Levels of Regulation. Infect Immun 76(6): Visel A, Blow M, Li Z, Zhang T, Akiyama J, Holt A, Plajzer-Frick I, Shoukry M, Wright C, Chen F et al ChIPseq accurately predicts tissue-specific activity of enhancers. Nature 457(7231): Wilbanks E, Facciotti M Evaluation of Algorithm Performance in ChIP-Seq Peak Detection. PLoS ONE 5(7): e Yaniv M The 50th anniversary of the publication of the operon theory in the Journal of Molecular Biology: past, present and future. Journal of molecular biology 409: 1-6. Zhang X, Robertson G, Krzywinski M, Ning K, Droit A, Jones S, Gottardo R PICS: probabilistic inference for ChIP-seq. Biometrics 67: Zhang Y, Liu T, Meyer C, Eeckhoute J, Johnson D, Bernstein B, Nusbaum C, Myers R, Brown M, Li W et al Model-based Analysis of ChIP-Seq (MACS). Genome Biology 9(9): R137. Zhao Y, Granas D, Stormo G Inferring Binding Energies from Selected Binding Sites. PLoS Comput Biol 5(12): e Zinzen R, Senger K, Levine M, Papatsenko D Computational models for neurogenic gene expression in the Drosophila embryo. Current biology : CB 16(13):

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