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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. [email protected] [email protected] Kolchanov N.A., IC&G, BGRS 2000.

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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

[email protected]

[email protected]


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.


Kolchanov N.A., IC&G, BGRS 2000

3

Basic modules of the GeneExpress system

http://wwwmgs/mgs/systems/geneexpress/


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.


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:


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


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


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


Kolchanov N.A., IC&G, BGRS 2000

INTERFACE OF NUCLEOSOME SITE RECOGNITION PROGRAM

8

http://wwwmgs.bionet.nsc.ru/mgs/programs/recon/


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


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


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


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 )


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


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


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)


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


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


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


Kolchanov N.A., IC&G, BGRS 2000

SCHEME OF INITIATIATION COMLEX ASSEMBLING AND FUNCTIONING

19

(Nikolov and Burley, 1997)


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 ]


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


Kolchanov N.A., IC&G, BGRS 2000

RECOGNITION FUNCTION PROFILE FOR NUCLEOSOME SITES OF THE HUMAN HYDROXIMETHYLBILANSYNTHETASE

GENE (AC M95623)

22


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


Kolchanov N.A., IC&G, BGRS 2000

RECOGNITION FUNCTION PROFILE OF NUCLEOSOME SITES OF MOBILE ELEMENT P1 IN Drosophila melanogaster

24


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(

)


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


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


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


Kolchanov N.A., IC&G, BGRS 2000

PROFILE FOR NUCLEOSOME SITE

29

a)

Twist,

degrees

Twist

Position,

bp

Inclination,

degrees

b)

Inclination

Position,

bp


Kolchanov N.A., IC&G, BGRS 2000

GRADIENTS FOR NUCLEOSOME SITE

30

Rise,

angstrom

a)

Rise

Position,

bp

Tip,

degrees

b)

Tip

Position,

bp


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


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


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.


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


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


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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