Modeling of Chromatin

Theoretical models of chromatin fibers and their simulated AFM images support the view that extended chromatin fibers are irregular three-dimensional arrays of nucleosomes connected by straight linkers... 

The insight from AFM images may be greatly boosted by sophisticated image analysis. Fritzsche and Henderson [30,31] have extracted cross-sections of nucleosomes at half-maximum height and have fitted them to virtual ellipsoids. These ellipsoids had relatively smooth perimeter and an aspect ratio of 1.2 1.4 moreover, the orientation of the ellipsoids was correlated with the direction of the fiber axis, with more than 50% of nucleosomes aligned with the axis. While this orientation effect may result from surface interactions, as discussed by the authors themselves, it may also represent an actual, and structurally important, feature of fiber structure. Ellipsoid-shaped nucleosomes have been reported in electron EM studies [32,33], and have been predicted in models of chromatin... 

Widom, J. (1989) Toward a unified model of chromatin folding. Atmu. Rev. Biophys. Biophys. 

The nucleosome core particle NCP (Fig. 4) is the first organisation level of chromatin, constituent of chromosomes. It is the "bead" in the "beads on a string" model of chromatine. 

In order to be acceptable models of chromatin structure need to be consistent with observations made by different methods as summarized in Table 2. Due to the lack pf direct information on the exact location of histones H1/H5 and disposition of the linker DNA the results do not lead to a unique model however, they provide evidence to rule out some of the existing models. 

Fig. 5. Solenoid model of the 30-nm filament of chromatin, where the disks represent nucleosomes and the dark line unbound DNA.

A model called histone code theory includes more aspects of chromatin regulation which have been identified. The histone code theory predicts that histone acetylation and other posttranslational histone modifications serve as binding sites for regulatory proteins which mediate processes like gene transcription upon recruitment (see Fig. 2b) [3]. In this context histone modifications can be understood as... 

Balhom, R. (1982). A model for the structure of chromatin in mammalian sperm. J. Cell. Biol. 93 298-305. 

Recently, a low-resolution model of the chromatin core particle has been derived from a combination of single-crystal X-ray diffraction and electron microscopic data (Finch et al., 1977). The particle is described as a flat cylinder 110 A in diameter and 57 A in height. A similar shape and similar dimensions were found to be consistent with the low-angle neutron scattering from core particles in solution (Pardon et al., 1977 Suau et al., 1977). Some conclusions may be drawn concerning the conformation of the DNA. Presumably, the strong 28 A periodicity apparent in the crystal data (Finch et al., 1977) corresponds to the pitch of the DNA superhelix wound about the histone core. X-Ray and spectroscopic data suggest that the DNA super-... 

Although the higher order structure of chromatin is still not well understood, two models have been suggested and supported by experimental evidence (for references, see Felsenfeld, 1978 Chambon, 1978). One is the solenoid model of Finch and Klug (1976), obtained by supercoiling the chromatin thread, and the other model is the superbead model (Renz et al., 1977). Each may represent a different... 

Figure 1. Hierarchical model of chromosome structure, (a) In interphase cells, DNA is packed in a nucleus as forming nucleosome and chromatin, (b) DNA forms nucleosome structure together with core histone octamer, which is then folded up into 30nm fiber with a help of linker histone HI. This 30 nm fiber is further folded into 80 nm fiber and 300 nm loop structures in a nucleus. In mitosis, chromosome is highly condensed. Proteins which are involved in each folding step are indicated above and non-protein factors are indicated below, (c) The amino acid sequences of histone tails (H2A, H2B, H3 and H4) are shown to indicate acetylation, methylation and phosphorylation sites. (See Colour Plate 1.)...

Lu W, Peterson R, Dasgupta A, Scovell WM (2000) Influence of HMG-1 and adenovirus oncoprotein ElA on early stages of transcriptional preinitiation complex assembly. J Biol Chem 275 35006-35012 Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucle-osome core particle at 2.8 A resolution. Nature 389 251—260 Lusser A, Kadonaga JT (2004) Strategies for the reconstitution of chromatin. Nat Methods 1 19-26 Maeshima K, Laemmli UK (2003) A two-step scaffolding model for mitotic chromosome assembly. Dev Cell 4 467-480... 

Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y (2006) Histone demethylation by a family of JmjC domain-containing proteins. Nature 439 811-816 van Holde K, Yager T (2003) Models for chromatin remodeling a critical comparison. Biochem Cell Biol 81 169-172... 

Two approaches are usually taken to study the effect of the association of DNA binding anticancer drugs upon the structure of chromatin and nucleosome. The first one is reconstitution of the model nucleosome in the presence of the drugs. This has been reported earlier in the case of mithramycin (Fox and Cons, 1993 Carpenter et al., 1993). In our laboratory, so far we have taken the second approach of comparing the association of the anticancer drugs with isolated chromatin at various levels. 

DNA IN CHROMATIN FROM GENOME-WIDE SEQUENCE ANALYSIS TO THE MODELING OF REPLICATION IN MAMMALS... 

From Sequence Analysis to the Modeling of the Chromatin Tertiary Structure Perspectives Acknowledgments References... 

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