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N.A. Kolchanov and V.G. Levitsky

Kolchanov N.A., IC&G, BGRS 2000. 1. NUCLEOSOME FORMATION SITES: CODING, ORGANIZATION AND FUNCTION. Institute of Cytology and Genetics of SB RAS, Novosibirsk, Russia. N.A. Kolchanov and V.G. Levitsky. kol@bionet.nsc.ru. levitsky@bionet.nsc.ru. Kolchanov N.A., IC&G, BGRS 2000.

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N.A. Kolchanov and V.G. Levitsky

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  1. Kolchanov N.A., IC&G, BGRS 2000 1 NUCLEOSOME FORMATION SITES: CODING, ORGANIZATION AND FUNCTION Institute of Cytology and Genetics of SB RAS, Novosibirsk, Russia N.A. Kolchanov and V.G. Levitsky kol@bionet.nsc.ru levitsky@bionet.nsc.ru

  2. Kolchanov N.A., IC&G, BGRS 2000 160 - 240 bp 5’ 3’ NUCLEOSOME POSITIONING CODE: COMMON FEATURES 2 A nucleosome is schematically considered as an octameric histone core, with one and a half circuits of 146 bp double helix DNA coiled around this core. Nucleosomes are distributed along genome DNA in average distance of about 160-240 bp.

  3. Kolchanov N.A., IC&G, BGRS 2000 3 Basic modules of the GeneExpress system http://wwwmgs/mgs/systems/geneexpress/

  4. Kolchanov N.A., IC&G, BGRS 2000 4 http://wwwmgs.bionet.nsc.ru/mgs/systems/nucleosom/ Levitsky V.G., Ponomarenko M.P., Ponomarenko J.V., Frolov A.S., Kolchanov N.A., Nucleosomal DNA property database. Bioinformatics, 1999, 15, 582-592.

  5. Kolchanov N.A., IC&G, BGRS 2000 ( 1 ) ( 2 ) f f 1 , j 1 , j Nucleosome sites 2. Random sequences 1. 1) CAACTGCCAC { } 1) TGCACAGCCC { } ( 1 ) ( 2 ) f f ………………… …………………. N , j N , j N) CAGTGGTTAA { } N) GTGGCCTCAA { } ( 1 ) f f +1 N N 1 , = , å å - j = - + - ( 2 ) ( 1 ) 1 ( 2 ) ( 1 ) ( f ) * {[ f ( ) * ( f f )] * S * [ f f ]} 1 = 2 j j j j , k k k 2 R ( 2 ) f = = f j 1 k 1 -1 , = . • NUCLEOSOME RECOGNITION FUNCTION BASED ON THE DISCRIMINANT ANALYSIS OF DINUCLEOTIDE FREQUENCIES 5 fj - frequency of a definite dinucleotide in the k-th region of a nucleosome site, where к = [j/16] +1. K is the number of regions , into which a nucleosome site is partitioned Partitions of a nucleosome site into blocks k=1 K 8 8 10 8 31 11 8 11 31 8 10 8 8 5’ 3’ -60 -40 -20 0 +20 +40 +60 Two samples of DNA sequences:

  6. Kolchanov N.A., IC&G, BGRS 2000 The average frequencies for two samples 1 å g g ( ) f g ( ) * f = =1, 2 , N n , i i = n 1 Covariations 1 N å g g g g - - g ( ) ( ) ( ) ( ) ( ) S * {( f f ) * ( f f )} = n , i i n , j j i , j - N 1 = n 1 United covariation matrix S [ ] ( 1 ) ( 2 ) [ S ] [ S ] + = 5a

  7. Kolchanov N.A., IC&G, BGRS 2000 SITES RANDOM DISTRIBUTIONS OF RECOGNITION FUNCTION VALUES, BASED ON DINUCLEOTIDE FREQUENCIES, FOR NUCLEOSOME SITES AND RANDOM SEQUENCES 6 Probability 0.25 0.2 0.15 0.1 0.05 0 -2.44 -1.84 -1.25 -0.65 -0.05 0.55 1.14 1.74 2.34 2.94 Recognition function value

  8. Kolchanov N.A., IC&G, BGRS 2000 30% False positive rate 25% 20% 15% 10% 5% False negative rate 0% 0% 5% 10% 15% 20% 25% 30% FALSE POSITIVES AND FALSE NEGATIVES UNDER NUCLEOSOME SITE RECOGNITION BASED ON DINUCLEOTIDE FREQUENCIES 7

  9. Kolchanov N.A., IC&G, BGRS 2000 INTERFACE OF NUCLEOSOME SITE RECOGNITION PROGRAM 8 http://wwwmgs.bionet.nsc.ru/mgs/programs/recon/

  10. Kolchanov N.A., IC&G, BGRS 2000 Donor sites Acceptor sites Recognition function value Recognition function value Intron Exon Exon Intron ... 0.8 1.2 1 0.6 0.8 0.4 0.6 0.2 0.4 0 0.2 -0.2 0 -150 -100 -50 0 50 100 -150 -100 -50 0 50 100 150 150 Position relative by splicing center site, bp Position relative by splicing center site, bp RECOGNITION FUNCTION PROFILE FOR NUCLEOSOME SITES IN HUMAN 9

  11. Kolchanov N.A., IC&G, BGRS 2000 Donor sites Acceptor sites . Recognition function value Recognition function value Exon Intron Intron Exon ... 1 1.2 1 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 0 -150 -100 -50 0 50 100 150 -150 -100 -50 0 50 100 150 Position relative by splicing center site, bp Position relative by splicing center site, bp 10 RECOGNITION FUNCTION PROFILE FOR NUCLEOSOME SITES IN RODENTS

  12. Kolchanov N.A., IC&G, BGRS 2000 Donor sites Acceptor sites Recognition function value Recognition function value Exon Intron Intron Exon ... 1 1 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 0 -0.2 -0.2 -0.4 -0.4 -0.6 -0.6 -150 -100 -50 0 50 100 150 -150 -100 -50 0 50 100 150 Position relative by splicing center site, bp Position relative by splicing center site, bp RECOGNITION FUNCTION PROFILE FOR NUCLEOSOME SITES IN Drosophila melanogaster 11

  13. Kolchanov N.A., IC&G, BGRS 2000 INSERTION OF INTRON INTO THE GENE CODING REGION ALLOWS AN EFFICIENT NUCLEOSOME FORMATION SITE TO BE INSTALLED 12 Nucleosome formation potential Gene coding region Insertion of intron Nucleosome formation potential Nucleosomal site exon 1 intron exon 2 The eukaryotic genes exon-intron structure can be determined by the nucleosomal organisation of the chromatin and related characteristics of gene expression regulation. (Solovyev V.V., Kolchanov N.A. , 1985, Dokl Akad Nauk SSSR, 284, 232-237 )

  14. Kolchanov N.A., IC&G, BGRS 2000 Recognition function value Transcription start 5 4 3 2 1 0 -1 -2 -3 HSS HSS HSS -4 -5 0 4000 6000 8000 1000 2000 3000 5000 7000 9000 10000 Position, bp RECOGNITION FUNCTION PROFILE FOR NUCLEOSOME SITES IN THE 5' SPACER REGION OF THE CHICKEN -GLOBIN GENE 13

  15. Kolchanov N.A., IC&G, BGRS 2000 Transcription starts Recognition function value 4 3 2 1 0 -1 -2 -3 -4 -5 4500 5000 5500 6000 7000 6500 Position, bp RECOGNITION FUNCTION PROFILE FOR NUCLEOSOME SITES IN ADH GENE OF Drosophila melanogaster 14

  16. Kolchanov N.A., IC&G, BGRS 2000 RECOGNITION FUNCTION PROFILE FOR NUCLEOSOME SITES FOR BITHORAX COMPLEX FRAGMENT IN Drosophila melanogaster 15 Recognition function value Transcription starts 4 3 2 1 0 -1 -2 -3 -4 -5 0 5000 10000 15000 20000 25000 30000 Position, bp Genes: S-adenosylhomocysteinhydrolase and a part of the Abd-B gene (with two alternative transcription starts)

  17. Kolchanov N.A., IC&G, BGRS 2000 Recognition function value Transcription start 1 0.8 0.6 0.4 0.2 0 -0.2 -0.4 -600 -500 -400 -300 -200 -100 0 100 200 300 400 500 600 Position, bp RECOGNITION FUNCTION PROFILE FOR PROMOTER REGION OF HUMAN GENES 16

  18. M= -1.5 14% Kolchanov N.A., IC&G, BGRS 2000 12% 10% 8% 6% 4% 2% 0% -4 -3 -2 -1 0 1 2 3 4 M= -0.7 14% 12% 10% 8% 6% 4% 2% 0% -4 -3 -2 -1 0 1 2 3 4 M= +0.7 14% Nucleosomal Site 12% 10% 8% 6% 4% 2% 0% DISTRIBUTION OF RECOGNITION FUNCTION PROFILE FOR NUCLEOSOME SITES OF PROMOTERS OF HUMAN GENES WITH DIFFERENT EXPRESSION PATTERNS promotors of house keeping genes 17 promotors of widly expressed genes promotors of Tissue-specific genes -4 -3 -2 -1 0 1 2 3 4

  19. Kolchanov N.A., IC&G, BGRS 2000 RECOGNITION FUNCTION PROFILE FOR NUCLEOSOMAL SITES OF HUMAN GENES 18 Tissue-specific genes "Housekeeping" genes delta-globin gene ubiquitin gene Transcription start Transcription start primary transcript primary transcript prealbumin gene chromosomal protein HMG 17 gene Transcription start Transcription start primary transcript primary transcript

  20. Kolchanov N.A., IC&G, BGRS 2000 SCHEME OF INITIATIATION COMLEX ASSEMBLING AND FUNCTIONING 19 (Nikolov and Burley, 1997)

  21. Kolchanov N.A., IC&G, BGRS 2000 SCHEMATIC REPRESENTATION OF MMTV PROMOTER DNA WRAPPED AROUND THE HISTONE OCTAMER WITH THE APPROXIMATE LOCATION OF GLUCOCORTICOID RECEPTORS AND TRANSCRIPTION FACTORS NF-1 AND OTF-1 20 [Mathias Truss et. al. ,The EMBO Jornal vol. 14 no.8 pp. 1737-1751, 1995 ]

  22. Kolchanov N.A., IC&G, BGRS 2000 NUCLEOSOME ORGANIZATION OF HSP27 GENE IN D.melanogaster 21 Nucleosome Quivy J.P., Backer P.B. The architecture of the heat-inducible Drosophila hsp27 promoter in nuclei J.Molec.Biol.V. 256. 1996 P. 249-263, 96174473

  23. Kolchanov N.A., IC&G, BGRS 2000 RECOGNITION FUNCTION PROFILE FOR NUCLEOSOME SITES OF THE HUMAN HYDROXIMETHYLBILANSYNTHETASE GENE (AC M95623) 22

  24. Kolchanov N.A., IC&G, BGRS 2000 Nucleosomebinding sites TATA Random sequences HISTOGRAMS OF TWIST ANGLE MEAN VALUES FOR INVERTEBRATE TATA-BOXES, RANDOM SEQUENCES, AND NUCLEOSOME BINDING SITES 23

  25. Kolchanov N.A., IC&G, BGRS 2000 RECOGNITION FUNCTION PROFILE OF NUCLEOSOME SITES OF MOBILE ELEMENT P1 IN Drosophila melanogaster 24

  26. Kolchanov N.A., IC&G, BGRS 2000 LOCAL CONFORMATIONAL PARAMETERS OF DNA DOUBLE HELIX 25 ) h q Coordinate frame Tip ( Inclination( ) s w k Opening ( Propeller twist( Buckle( ) ) ) W r t Twist( ) Roll( ) Tilt( )

  27. Kolchanov N.A., IC&G, BGRS 2000 Twist ( ) W DISCRIPTION OF THE DINUCLEOTIDE DEPENDENT HELICAL TWIST ANGLE VALUE IN THE KNOWLEDGE BASE 26 DINUCLEOTIDE AA 38.90 AT 33.81 AG 32.15 AC 31.12 ** TA 33.28 TT 38.90 TG 41.41 * TC 41.31 GA 41.31 GT 31.12 ** GG 34.96 GC 38.50 CA 41.41 * CT 32.15 CG 32.91 CC 34.96 // MI P0000001 MN Conformational MD B-DNA ML dinucleotide step PN Twist PM Calculated by Sklenar, PM and averaged by Ponomarenko PV TwistCalc PU Degree

  28. Kolchanov N.A., IC&G, BGRS 2000 t Tilt ( ) DISCRIPTION OF THE DINUCLEOTIDE DEPENDENT TILT ANGLE VALUE IN THE KNOWLEDGE BASE 27 DINUCLEOTIDE AA 1.9 * AT 0.0 AG 1.3 AC 0.3 TA 0.0 TT 1.9 * TG 0.3 TC 1.7 GA 1.7 GT -0.1 ** GG 1.0 GC 0.0 CA 0.3 CT 1.3 CG 0.0 CC 1.0 // MI P0000016 MN Conformational MD DNA/protein-complex ML dinucleotide step PN Tilt PM Averaged for X-rays PV TiltCompl PU Degree

  29. Kolchanov N.A., IC&G, BGRS 2000 SCHEME LOCATION OF THE REGION, DIFFERING BY DNA BENDING, AT THE SURFACE OF HISTONE OCTAMER 28 Profile for the Melting temperature of nuclosome DNA, window size is 7 bp Melting temperature, degrees 71 70.5 70 69.5 69 68.5 68 67.5 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100 Position relatively the site center (diads), bp

  30. Kolchanov N.A., IC&G, BGRS 2000 PROFILE FOR NUCLEOSOME SITE 29 a) Twist, degrees Twist Position, bp Inclination, degrees b) Inclination Position, bp

  31. Kolchanov N.A., IC&G, BGRS 2000 GRADIENTS FOR NUCLEOSOME SITE 30 Rise, angstrom a) Rise Position, bp Tip, degrees b) Tip Position, bp

  32. Kolchanov N.A., IC&G, BGRS 2000 f - the partial recognizing procedure for sites of the given type: n IF f (S)>0, THEN the S =(s ...s ...s ) is the recognized site; n a i b the recognition values are normalized as: f (S) n N f ( Site ) å n n = 1 ; (for sites) N = n 1 N f ( Rand ) å n n = - 1 ; (for random sequences) N = n 1 Then the mean recognition procedure is defined as follows N f ( S ) å n ab = F ( S ) , N ab Site N = n 1 IF {F (S)>0}, THEN {S is the site }. N f f f ... f 1 3 2 N F N CALCULATION OF THE MEAN RECOGNITION SCORE 31

  33. Kolchanov N.A., IC&G, BGRS 2000 0,3 0,2 probability, p 0,1 0 -4,1 -2,1 -0,1 1,85 3,84 recognition score DISCRIMINANTION ABILITY OF THE NUCLEOSOME SITE RECOGNITION SCORE BASED ON THE CONFORMATIONAL AND PHYSICAL/CHEMICAL PROPERTIES 32

  34. Kolchanov N.A., IC&G, BGRS 2000 NUCLEOSOME POSITIONING CODE: COMMON FEATURES 33 The elements (or the signals) of nucleosomal code are dinucleotides (oligonucleotides) determining local conformational (physicochemical) nucleosome site features, necessary for interaction with core histones Nucleosomal code is point-wise: only particular groups of positions are used for coding genetic messages on local conformational DNA features, significant for interaction of nucleosome sites with core histone. Besides, these groups located in a definite (unfixed) distance.

  35. Kolchanov N.A., IC&G, BGRS 2000 NUCLEOSOME POSITIONING CODE: COMMON FEATURES 34 Nucleosomal code is extremely degenerated: very differing DNA sequences that interact with histone octamer are recognized Nucleosomal code is point-wise: it provides the possibility of overlapping with the other types of codes

  36. Kolchanov N.A., IC&G, BGRS 2000 NUCLEOSOME POSITIONING CODE: COMMON FEATURES 35 Nucleosomal code is extremely excessive: there exists a huge variety of the context-dependable conformational and physicochemical signals that could be used for the coding of DNA sequences packaged into a nucleosome Positioning of the core octamer at the definite DNA site is performed on the base of specific subset of signals located in particular set of positions Signal involved in the coding of the partucular nucleosome formation Signal is not used for coding formation of the partucular nucleosome formation due to constraints imposed by other codes Site 1 Site 2

  37. Kolchanov N.A., IC&G, BGRS 2000 ACNOWLEDGEMENT 36 The authors are grateful to Dr. M.P. Ponomarenko, Dr. O.A. Podkolodnaya, J.V. Ponomarenko for participance and help in work

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