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540a

Role of Histone Tails and Linker Histone in Chromatin Folding

Gaurav Arya and Tamar Schlick. Department of Chemistry and Courant Institute of Mathematical Sciences, New York University, 31 Washington Place, Room 1021 Main, New York, NY 10003

Eukaryotic double-stranded DNA achieves cellular compaction through several hierarchical levels of organization. The most fundamental of these involves wrapping of DNA around protein aggregates known as nucleosomes, which comprise of two copies each of the positively charged histone chains H2A, H2B, H3 and H4. The resulting "bead-on-a-string" DNA-nucleosome complex folds further at physiological salt conditions, and in the presence of a fifth histone known as the linker histone (H1 or H5), into the venerable 30-nm chromatin fiber. Electrostatic arguments along with the emerging "histone code" hypothesis suggest that the N-termini of core histones, or the so-called histone tails, are crucial to the maintanence and regulation of chromatin [1]. Exactly how this is achieved through a combination of physical and biological factors is presently unclear.

Here, we present a new mesoscopic model of oligonucleosome which incorporates flexible histone tails to elucidate the physical role of each histone tail and the linker histone in chromatin folding [2]. The nucleosome core is treated as a rigid electrostatic surface with a set of uniformly distributed discrete charges; the linker DNA is represented by the standard discrete elastic chain model; and the histone tails are treated as chains of coarse-grained beads where each bead represents five amino acid residues. Appropriate charges and force field parameters are assigned to each histone chain so as to reproduce its configurational and electrostatic properties. The model reproduces experimental results better than its predecessors which model the histone tails as rigid entities. In particular, it correctly accounts for salt-dependent conformational changes in the histone tails and the diffusion and sedimentation coefficients of nucleosomal arrays.

An end-transfer configurational-bias Monte Carlo approach [3] that efficiently samples possible conformational states of oligonucleosomes provides the positional distribution of histone tails around the nucleosome cores and their interactions within the fiber at different salt milieus [4]. Analyses indicate that the H4 histone tails are the most important tails in terms of mediating internucleosomal interactions, especially in linker histone-compacted chromatin, followed by the H3, H2A, and H2B tails. In addition to mediating internucleosomal interactions, the H3 histone tails crucially screen electrostatic repulsion between the entering/exiting DNA linkers. The H2A and H2B tails distribute themselves along the periphery of the chromatin fiber and are thus important for mediating fiber/fiber interactions. The primary function of the linker histones is to decrease the internucleosomal distance, and the nucleosome triple and quadruplet angles, resulting in highly compact chromatin with a notably different nucleosome/nucleosome interaction pattern than that obtained in linker-histone deficient chromatin.

[1] G. Felsenfeld and M. Groudine, Nature 421, 448 (2003).

[2] G. Arya, Q. Zhang, and T. Schlick, Biophys. J. 91, 133 (2006)

[3] G. Arya and T. Schlick, J. Chem. Phys., submitted (2006)

[4] G. Arya and T. Schlick, Proc. Natl. Acad. Sci. USA, 103, 16236 (2006)



Web Page: monod.biomath.nyu.edu/~ga37