Proc. Natl. Acad. Sci. USA Vol. 75, No. 9, pp. 4184-4188, September 1978 Biochemistry

Primary organization of nucleosome core particle of chromatin: Sequence of histone arrangement along DNA (crosslinking of proteins to DNA/sequencing)

ANDREI D. MIRZABEKOV*, VALENTIN V. SHICK, ALEXANDER V. BELYAVSKY, AND SERGEI G. BAVYKIN Institute of Molecular Biology, Academy of Sciences of the U.S.S.R., Moscow 117312, U.S.S.R.

Communicated by W. Engelhardt, June 6,1978 A high-resolution map for the arrangement of ABSTRACT histones along DNA in the nucleosome core particle has been determined by a sequencing procedure based on crosslinking histones to the 5'-terminal DNA fragments produced by scission of one DNA strand at the point of crosslinking. The position of histones on DNA has been identified by measuring the length of crosslinked DNA fragments. The results demonstrate that each of the histones is arranged within several adjacent or dispersed DNA segments of a little less than 10 nucleotides in length. Histone-free intervals are located between these segments at the regular distances of about (1O). nucleotides from the 5' end of the DNA and are likely to face one side of the DNA helix. Histones appear to be arranged in a similar manner on both DNA strands and do not form "locks" around DNA. A linearized model of the core particle is proposed.

The periodic structure of chromatin now appears to be well established (for review, see refs. 1 and 2). A repeat unit of chromatin, termed the nucleosome, is made up of an octamer aggregate of histones containing pairs of each of the four main types, H2A, H2B, H3, and H4, which together with histone HI (3) is complexed with DNA of a variable length (150-240 base pairs). The basic structural element of the nucleosome in all cell types seems to be a core particle containing the histone octamer and DNA of about 140 base pairs in length (4, 5). Recent studies of the core particle crystals suggest that its structure is a flat disc of dimensions 110 X 110 X 57 A; about 1.75 turns of DNA in the B form are wound around the protein core (6). The proximity of histones in chromatin has been revealed by histone-histone crosslinking experiments (for review, see ref. 1). Histones H3 and H4 appear to play a central part in nucleosome formation (7) as first suggested by Kornberg (8). In the nucleosome the DNA sites separated by 10-nucleotide intervals are exposed to the action of different nucleases (7, 9). As determined by methylation experiments (10, 11), histones are partly buried in the major groove and leave the minor groove of DNA well exposed. Here we report a high-resolution map for the arrangement of histones along the core DNA determined by a sequencing procedure (11) in which histones were crosslinked to DNA within the core (12). Crosslinking causes the specific scission of one DNA strand at the point of crosslinking and the attachment of only the 5'-terminal DNA fragment to histones. The size of the single-stranded DNA fragments crosslinked to each histone species has been measured to identify the position of histones on one strand of the core DNA from its 5' end. A fairly clear picture of the detailed organization of histones has emerged from this map. Preliminary results of this work have been published elsewhere (11).

MATERIALS AND METHODS Crosslinking Histones to DNA. The core particles were prepared from Hl-depleted chromatin of mouse Ehrlich ascites tumor cells as described (3, 11). The core particles (0.5 mg/ml) were methylated (about 0.5% of DNA bases) with 5 mM dimethyl sulfate in 37.5 mM sodium cacodylate, pH 7.1/0.1 mM EDTA/0.1 mM ethylene glycol-bis(f-aminoethyl ether)N,N-tetraacetic acid (EGTA) at 0° for 18 hr. The material was dialyzed against 20 mM potassium phosphate, pH 6.8/2.5 mM (ethylenedinitrilo)tetraacetic acid (EDTA)/2.5 mM EGTA. Depurinization (about 0.1% of DNA bases) was carried out for 8 hr at 450 in this buffer in the presence of 1 mM phenylmethylsulfonyl fluoride. The sample was dialyzed against 100 mM potassium phosphate, pH 6.8/0.1 mM EDTA/0.1 mM EGTA at 40; 0.05 vol of a freshly prepared 0.5 M NaBH4 solution was added and the reduction with NaBH4 was carried out at 40 for 30 min. Finally, the crosslinked sample was dialyzed against distilled water and lyophilized. Isolation and Labeling of Crosslinked Histones and DNA. In order to remove most of the unbound histones, the crosslinked cores were dissolved in 1 M NaCl/5 M urea/20 mM sodium phosphate, pH 7.0/1% cetyltrimethylammonium bromide, and the DNA with attached histones was reprecipitated three times as the cetyltrimethylammonium salt by diluting the solution with 4 vol of 1.9 M urea/20 mM sodium phosphate, pH 7.0 (13). DNA was converted to the sodium salt by reprecipitation from 1 M NaCl with 3 vol of ethanol and dissolved in distilled water. In one portion of the solution, crosslinked histones were labeled with a25I (10 Ci/mg) by the iodine monochloride method in the presence of 1% sodium dodecyl sulfate (14). In another portion, DNA was labeled at its 5' ends in the presence of [,y-32P]ATP (200-300 Ci/mmol) and polynucleotide kinase (15). In order to remove most of the noncrosslinked DNA, the 32P-labeled sample was dissolved in 100 ,ul of 20 mM sodium cacodylate, pH 7.1/1% sodium dodecyl sulfate/0.05% bovine serum albumin. The complex of sodium dodecyl sulfate with crosslinked histones and albumin and the sodium dodecyl sulfate itself were precipitated with 50 .l of 4.5 M NaCl (16). After incubation at 40 for 1 hr the precipitate was centrifuged and the material was reprecipitated under the same conditions once more. Gel Electrophoresis. The size of DNA fragments crosslinked to each histone fraction was determined in two systems of two-dimensional gel electrophoresis. Electrophoresis was carried out on sodium dodecyl sulfate discontinuous polyacrylamide slab gels with the buffer system of Laemmli as described by Weintraub et al. (17). The crosslinked preparations were dissolved in sample buffer containing 7 M urea, and the DNA

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Abbreviations: EGTA, ethylene glycol-bis(fl-aminoethyl ether)N,N-tetraacetic acid; EDTA, (ethylenedinitrilo)tetraacetic acid. * To whom all correspondence should be addressed. 4184

Biochemistry: Mirzabekov et al. was denatured at 1000 for 1 min. The 125I-labeled histone andl [32P]DNA-labeled crosslinked samples were electrophoresed in the first direction in the adjacent slots of a 6% stacking/15% separating slab gel (16 X 16 X 0.15 cm) in the presence of 7 M urea until bromphenol blue migrated 9 cm. In order to release crosslinked histones, the gel strip containing 125I-labeled histones was cut out of the gel, washed with 66% formic acid and twice with 66% formic acid/2% diphenylamine for 45 min each time, and then incubated for 20 min at 70° to hydrolyze DNA (12). The strip was then washed for 30 min with 66% formic acid three times, with distilled water until neutral pH, and twice with the buffer of stacking gel. The strip was copolymerized with a 6% stacking gel on a 15% separating polyacrylamide slab gel (35 X 16 X 0.2 cm) and the released histones were electrophoresed in the second direction with 100 gg of unlabeled histones. The gel was fixed in 20% trichloroacetic acid and autoradiographed. The gel strip containing 32P was cut out of the first-dimension gel and washed twice for 30 min each time with the concentrating urea-free buffer and copolymerized with a 6% stacking gel lacking urea on a 20% separating polyacrylamide denaturing gel (16 X 16 X 0.2 cm) containing 7 M urea. Sample buffer (1.5 ml) containing 2 mg of DNase-free Pronase (Worthington), 1 mg of single-stranded standard DNA fragments (9), and 0.1 mg of the denatured core DNA was loaded on the gel. Electrophoresis was carried out until bromphenol blue reached the middle of the stacking gel; then the current was switched off for 2 hr to allow the Pronase to digest the histones (18), and thereupon electrophoresis was carried on. Sodium dodecyl sulfate was extracted from the gel twice with 70% isopropanol for 2 hr and once with water. DNA was stained with ethidium bromide (1 mg/ml in water), and the gel was dried and autoradiographed and the DNA bands were visualized in UV light.

RESULTS Chain Length of the Core DNA. The sizing of the core DNA was carried out by electrophoresis (Fig. 1) on nondenaturing and denaturing (containing 7 M urea) polyacrylamide slab gels as described (20). The following standard DNA fragments of known size were used for gel calibration: double stranded restriction fragments of OX174 RFI DNA and single-stranded DNA from the DNase I digestion of chromatin which contains a series of fragments of sizes that are integral multiples of 10 nucleotides (9). The length of the core single stranded and double-stranded DNA was found to be 145 ± 3 nucleotides and 146 ± 3 base pairs, respectively. The size distribution of the single-stranded core DNA calculated from the width of the band in the gel was about ±2 nucleotides. Treatment of the isolated native core DNA with endonuclease S1 specific for single-stranded nucleic acids (15) decreased the size of DNA on the denaturing gel by two nucleotides. This treatment also removed 32P-label from its 5' ends phosphorylated with Jjy32P]ATP and polynucleotide kinase (not shown). This suggests that the 5' ends of the core DNA protrude by two nucleotides. Two-nucleotide tails at 5' ends have been shown to be produced upon digestion of the chromatin DNA with micrococcal nuclease (2). Crosslinking. The DNA in the core particles was methylated with dimethyl sulfate (Fig. 2). Methylated purine bases (7-methylguanine and 3-methyladenine) labilize glycosyl bonds and can be therefore partly removed by incubation at 450 and neutral pH. Aldehyde groups formed in depurinated sites of DNA react with the e-amino groups of the neighboring lysine residues of histones and produce the Schiff base. As is well

Proc. Natl. Acad. Sc. USA 75 (1978)

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B

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-118a FIG. 1. Polyacrylamide gel analysis (electrophoresis in 8% polyacrylamide denaturing gel) of the core DNA chain length. Lanes: A, DNA of chromatin digested with DNase I; B, core DNA; C, core DNA treated with endonuclease Si; D, electrophoresis in 8% nondenaturing polyacrylamide gel of core DNA and the fragments of digestion of fX174 RFI DNA with restriction nucleases Hae III (a) or HindI (b) (19). Single- and double-stranded length in bases or base pairs is indicated at the left and right, respectively. DNA was stained with ethidium bromide.

known for DNA and RNA (for review, see ref. 21), this Schiff base effectively catalyzes the fl-elimination reaction that quantitatively breaks the phosphodiester bond at the 3'-OH group of depurinated nucleotides. As a result, histones become crosslinked only to the 5'-terminal fragments of DNA. The covalent bond between histones and DNA through the Schiff base can be stabilized by reduction with NaBH4. Under the conditions used, about 5% of histones (less than one histone molecule per two core DNA molecules) were randomly covalently bonded to DNA in the cores. The crosslinking procedure avoids drastic treatment, and we have not found any changes in electrophoretic mobility of the core particles or in the pattern of micrococcal nuclease (4, 5), DNase I (9, 15), or trypsin digestion of chromatin or the cores caused by crosslinking. Sizing Crosslinked DNA. Sizing the single-stranded 5'-terminal DNA fragments crosslinked to histones and the identification of these histones were carried out by electrophoresis in two two-dimensional polyacrylamide slab gel systems (Fig. 3). In both systems, electrophoresis of the crosslinked samples containing '25I-labeled histone or [32P]DNA in the first direction was carried out in adjacent slots of the denaturing gel. After the electrophoresis the strips containing '251-labeled histones and [32P]DNA were cut out separately. This separation occurs mainly according to the size of single-stranded DNA attached to histones. The strip containing 125I-labeled histones was treated with a formic acid/diphenylamine to hydrolyze DNA.

Proc. Natl. Acad. Sci. USA 75 (1978)

Biochemistry: Mirzabekov et al.

4186

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FIG. 2. Reactions leading to crosslinking of histones to DNA and scission of one DNA strand at the point of crosslinking. DMS, dimethyl sulfate; PU, a purine base.

identify the position of histones on one DNA strand measured in nucleotides from its 5' end and the width of the crosslinked DNA segments. The position of histone-free intervals is also shown in Table 1. No histones have been found to be crosslinked

Released DNA-free histones were electrophoresed in the second direction and identified according to their mobility (Fig. 3 A and B). The gel strip containing the [32P]DNA was treated with Pronase to digest histones (18). Released DNA fragments were sized (Fig. 3 C and D) by electrophoresis in the second direction in the presence of the unlabeled denatured core DNA and single-stranded standard DNA fragments of known size (9). There is an unambiguous correspondence between the spots that have the same histone notations and letter labels in the schemes of the autoradiograms (Figs. 3 B and D). These histone and DNA spots are located on the same vertical line of both autoradiograms in Fig. 3 A and C or B and D. They originate therefore from the same fractions of the crosslinked material separated in the first direction and thus correspond to histones and DNA fragments that are covalently bonded to each other. The discrete intensive spots in Fig. 3C corresponding to crosslinked DNA are spaced by intervals representing the DNA regions that are not crosslinked to histones. The size and the size distribution of the crosslinked DNA fragments can be calculated from Fig. 3C by comparing their mobility in the second direction with that of the standard DNA fragments (19). The measured size distribution of the 5'-terminal DNA fragments crosslinked to histones is shown in Table 1. These values directly

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DISCUSSION Ten-Nucleotide Spacing between Histone-Free Intervals in DNA. Histones are bound to DNA mainly through salt bridges between the charged phosphate groups of DNA and the lysine and arginine residues of histones. Our zero-length crosslinking procedure covalently binds the e-amino groups of lysines with the neighboring aldehyde groups in randomly distributed depurinated sites of DNA. Thus, the data of Table 1 describe the arrangement of lysine residues of histones along the core DNA. However, we believe that these data represent fully enough the whole primary organization of the core particle because arginines are distributed more or less evenly between lysines in histones (for review, see ref. 22). Table 1 and Fig. 3 show that histones are located within fairly discrete segments of DNA of a little less than 10 nucleotides in

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FIG. 3. Autoradiograms (A and C) and their diagrams (B and D) of labeled, crosslinked preparations of the core particles electrophoresed in two two-dimensional gel systems. After the separation in the first direction: (A) DNA was hydrolyzed and the released 125I-labeled histones were electrophoresed in the second direction; or (C) histones were digested and the released denatured [32P]DNA fragments were electrophoresed in the second direction in the presence of the unlabeled core DNA and standard DNA fragments. At the left of C is a photograph of the gel stained with ethidium bromide; at the right is its autoradiogram. The closed and open designations correspond to crosslinked and noncrosslinked molecules, respectively. Autoradiograms of only the lower parts of the gels containing radioactive material are presented.

Biochemistry: Mirzabekov et al.

Proc. Natl. Acad. Sci. USA 75 (1978)

Table 1. Size distribution of single-stranded 5'-terminal DNA fragments crosslinked to histones and position of histone-free intervals (see Fig. 3 C and D)

Histone H3a H2Aa H2Ba-b H3b-c H4a H2Ab and H3d H4b H4c H4d H2Bc H2Bd

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FIG. 4. Proposed similar arrangement of histones on both strands of the core DNA.

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This structure appears to be a general one because a similar histone arrangement has been determined for the core particles prepared from chromatin of Drosophila melanogaster (unpublished data). Each histone is covalently bonded to a few (from two to four) discrete DNA segments that are adjacent or are dispersed along the DNA. The known primary structure of histones (for review, see ref. 22) may give some insight into the mode of their interaction with DNA. The histones have an overall charge of about +20 due to the presence of 25-81 lysine and arginine residues and some acidic residues. The basic residues are distributed irregularly among the NHrterminal, COOH-terminal, and central regions of histones (22) and appear to interact predominantly with the negatively charged phosphate groups of DNA (24). Therefore, one histone molecule should be bound to at least 20 to 30 nucleotides or interact, by its different regions, with two to four or more discrete DNA segments of less than 10 nucleotides in length. Thus, the space in the two to four discrete segments is enough to bind entirely one rather than two histone molecules, and Table 1 appears therefore to identify only one of the two molecules of each histone type on one strand of the core DNA. This contradicts the first suggestion made above about the binding of the core histones to only one DNA strand and leads to the conclusion that two molecules of each histone type in the core are likely to be bound similarly to both antiparallel strands of the DNA. Fig. 4 shows (based on the data of Table 1) such an identical and symmetrical arrangement of histones on two strands of the DNA in the core particles. Symmetrical distribution of the DNase I cleavage sites in the core DNA (15, 23) and the probable presence of a dyad axis in the core (6) support such symmetrical models. Linearized Model of the Nucleosome Core Particle. One striking feature of the core structure appears when histones are arranged within 10-nucleotide repeat segments on the double-helical core DNA (Fig. 5). The DNA is assumed to be in the B form characterized by 10 nucleotides per turn. Histones are located along the sugar-phosphate backbone from the side of the major groove (10, 11). As a result of the DNA structure and lO-nucleotide regularity in the distribution of histones, the histone-free intervals on both DNA strands face the same side (the upper side in Fig. 5) of the DNA helix. One should apparently place these uncovered DNA regions on the surface facing outward toward solution when DNA with bound histones is folded into the nucleosome disc (6). In the model, different regions of histones (supposedly their NH2- and COOH-terminal

70 60 50 40 30

* Shown as nucleotide number. The dispersion of the measurements calculated from four experiments is about +3 nucleotides for shorter fragments and +5 nucleotides for longer fragments. t Corresponds to the approximate size (±3-5 nucleotides) of DNA in the intervals that are not crosslinked to histones and are located between the adjacent spots in Fig. 3C. Positions are determined from the longer electrophoretic gels (not shown).

length; the segments are spaced by intervals of a few nucleotides long. The DNA in the intervals is not crosslinked to histones and appear to be free of them. The intervals are well defined between short DNA fragments in Fig. 3 C and D from H2Bd up to H2Ab. They can be also discerned between longer fragments in the longer polyacrylamide gels. These histone-free intervals are located on the core DNA at a regular distance of about (10)n nucleotides from its 5' termini, in which n is an integer. In a similar manner, DNase I (9) and micrococcal nuclease (7) digest chromatin and the core particles at lO-nucleotide intervals. Moreover, the sites unprotected by histones and accessible to DNase I are localized on the core DNA at the same (10)n nucleotide distance from its 5' ends (15, 23). These results were confirmed by us with crosslinked core particles digested with DNase I (unpublished data). The good agreement between the crosslinking and nuclease digestion experiments leads to the conclusion that the histone-free intervals correspond to the nuclease accessible sites and represent regions in the core DNA that are indeed uncovered by histones. Arrangements of Histones on DNA Strands. Fig. 3C demonstrates that each segment of the core DNA is crosslinked to one histone except that segment 80-90 is attached to both H3c and H4a and 70-80 is attached to H2Ab and H3d. These data indicate that histones cover all of one DNA strand, except for nucleotides 1-20, in a specific manner, mainly without overlapping and therefore either bound primarily to only one strand of the core DNA or arranged in a similar manner on both DNA strands. This also presumably reflects the existence of predominantly one common structure for the core particles. 140

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FIG. 5. Linearized model of the nucleosome core particle. Histones are arranged along the sugar-phosphate backbone from the side of the major groove of DNA. The DNA is 145 bases long; two nucleotides from the 5' ends protrude. The distances are indicated in bases from the 5' end of each DNA strand.

4188

Biochemistry: Mirzabekov et al.

and central regions) cover a little less than one turn of the DNA helix and aquire therefore the shape of incomplete helical clamps. Because all the gaps in the histone clamps face the outer side of the core particle, histones do not form "locks" around DNA and thus allow the core particle to dissociate easily into the histone octamer and DNA. This is consistent with experiments demonstrating dissociation and reassociation of the crosslinked histone octamer with DNA (25) and might be essential for DNA replication and transcription. We have not yet identified the regions in the histones covalently bonded to each discrete DNA segment; neither have we determined the distribution of these regions between individual histone molecules. However, the arrangement of two histone molecules shown in Fig. 5 can be deduced from the probable existence of half nucleosomes (26, 27) made up of two heterotypic histone tetramers (17). Some histones are adjacent to each other in the model just across the major groove (H2A-H4, H2A-H3, H3-H4) and the minor groove (H2A-H2A, H2A-H2B, H2B-H4, H3-H3, H3-H4) or along one DNA strand (H2A-H2B, H2A-H3, H2A-H4, H2B-H3, H2B-H4, H3-H4). Other histones can be brought together upon DNA folding. All the dimers of histones H2A-H2B, H2A-H4, H2B-H4, H3-H3, and H3-H4 identified in histone-histone crosslinked chromatin and nucleosomes (for review, see ref. 1) are adjacent in the model across the major or minor grooves. Histones H3 and H4 occupy all the central part of the core DNA and may therefore alone reproduce some structural features of whole nucleosome upon reconstitution with DNA (7). We are grateful to Dr. K. G. Skryabin and his coworkers for generous gifts of [(y-32P]ATP and polynucleotide kinase, V. L. Karpov for the Drosophila core particles, and Prof. W. Engelhardt for criticism of the manuscript and encouragement. 1. Kornberg, R. D. (1977) Annu. Rev. Biochem. 46,931-954. 2. Felsenfeld, G. (1978) Nature 271, 115-122. 3. Varshavsky, A. Ya., Bakaev, V. V. & Georgiev, G. P. (1976) Nucleic Acids Res. 3, 477-492. 4. Sollner-Webb, B. & Felsenfeld, G. (1975) Biochemistry, 14, 2915-2920.

Proc. Nati. Acad. Sci. USA 75 (1978) 5. Axel, R. (1975) Biochemistry 14,2921-2925. 6. Finch, J. T., Lutter, L. C., Rhodes, D., Brown, R. S., Rushton, B., Levitt, M. & Klug, A. (1977) Nature 269,29-36. 7. Camerini-Otero, R. D., Sollner-Webb, B. & Felsenfeld, G. (1976)

Cell 8,333-347.

8. Kornberg, R. D. (1974) Science 184,868-871. 9. Noll, M. (1974) Nucleic Acids Res. 1, 1573-1578. 10. Mirzabekov, A. D., San'ko, D. F., Kolchinsky, A. M. & Melnikova, A. F. (1977) Eur. J. Biochem. 75,379-389. 11. Mirzabekov, A. D., Shick, V. V., Belyavsky, A. B., Karpov, V. L., & Bavykin, S. G. (1978) Cold Spring Harbor Symp. Quant. Biol. 42, 149-155. 12. Levina, E. S. & Mirzabekov, A. D. (1975) Dokl. Akad. Nauk USSR 221, 1222-1225. 13. Naktinis, V. J., Maleeva, N. E., San'ko, D. F. & Mirzabekov, A. D. (1977) Biochimia 42, 1783-1789. 14. Glover, J. S., Salter, D. N. & Sheperd, B. P. (1967) Biochem. J. 103, 120-129. 15. Noll, M. (1977) J. Mol. Biol. 116,49-71. 16. Varshavsky, A. Ya., Bakaev, V. V., Ilyin, Y. V., Bayev, A. A. & Georgiev, G. P. (1976) Eur. J. Biochem. 66,211-223. 17. Weintraub, H., Palter, K. & Van Lente, F. (1975) Cell 6, 85110. 18. Cleveland, D. W., Fisher, S. G., Kirshner, M. W. & Laemmli, U. K. (1977) J. Biol. Chem. 252, 1102-1106. 19. Sanger, F., Air, Y. M., Barrell, B. G., Brown, N. L., Coulson, A. R., Fiddes, J. C., Hutchinson, C. A., Slocombe, P. M. & Smith, M. (1977) Nature 265,687-695. 20. Maniatis, T., Jeffrey, A. & van de Sande, H. (1975) Biochemistry, 14,3787-3794. 21. Kochetkov, N. K., Budovsky, E. I., Sverdlov, E. D., Symukova, N. A., Turchinsky, M. F. & Shibaev, V. N. (1972) Organic Chemistry of Nucleic Acids (Plenum, New York), Part B, pp. 512-514. 22. Elgin, S. C. & Weintraub, H. (1975) Annu. Rev. Biochem. 44, 725-774. 23. Simpson, R. T. & Whitlock, J. P. (1976) Cell, 9,347-350. 24. Malchy, B. & Kaplan, H. (1974) J. Mol. Biol. 82,537-545. 25. Stein, A., Bina-Stein, M. & Simpson, R. T. (1977) Proc. Natl. Acad. Sci. USA 74,2780-2784. 26. Tsanev, R. & Petrov, P. (1976) J. Microsc. Biol. Cell 27, 1118. 27. Oudet, P., Spadtefora, C., & Chambon, P. (1978) Cold Spring Harb. Symp Quant. Biol. 42,301-312.

Primary organization of nucleosome core particle of chromatin: sequence of histone arrangement along DNA.

Proc. Natl. Acad. Sci. USA Vol. 75, No. 9, pp. 4184-4188, September 1978 Biochemistry Primary organization of nucleosome core particle of chromatin:...
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