A Tale of Histone Tails

Tamar Schlick

Chemistry, Mathematics, and Computer Sciences, New York University

Eukaryotic chromatin is the fundamental protein/nucleic acid unit that stores the genetic material. Understanding how chromatin fibers fold and unfold as well as details of their structure and dynamics on a range of spatial and dynamical scales is important for interpreting fundamental biological processes like DNA replication and transcription regulation.

Using a mesoscopic model of oligonucleosome chains and tailored sampling protocols, we elucidate the energetics of oligonucleosome folding/unfolding and the role of each histone tail in regulating chromatin structure. Simulations reveal unfolding of oligonucleosome at low salt due to strong electrostatic repulsion between linker DNAs, leading to the `bead-on-a-string' model. At higher salt, oligonucleosomes remain moderately folded due to a balance between the attractive inter-nucleosomal interactions (mediated by the histone tails) and repulsive interactions between the linker DNA. Furthermore, tail-mediated fiber/fiber interactions emerge as the oligonucleosome chain folds into more compact self interactions. The packing ratio of 5 nucleosomes per 11 nm for these models is in good agreement with in vitro chromatin measurements.

Analyses of the tail positional distributions reveal a broad spread of tail positions consistent with the dynamic and flexible nature of the tails. The H4 tails mediate the strongest inter-nucleosomal interactions due to their favorable location on the nucleosome core, especially at high salt; the H3 tails interact strongly with the parent linker DNA, which helps screen electrostatic repulsion between the linkers and assist in chromatin folding; the H2A and H2B tails mediate considerable fiber/fiber interactions. Upon adding linker histones, the chromatin fiber condense markedly.

These studies open the door to investigations of higher-order structures of compact chromatin and the biochemical modulation by altered histone tail charge (via acetylation, methylation, phosphorylation) of chromatin structure and genome accessibility.

Of Possible Interest

T. Schlick, Molecular Modeling: An Interdisciplinary Guide, Springer-Verlag, New York, 2002.

D. Beard and T. Schlick, ``Computational Modeling Predicts the Structure and Dynamics of the Chromatin Fiber", Structure 9: 105--114 (2001).

G. Arya, Q. Zhang, and T. Schlick, ``Flexible Histone Tails in a New Mesoscopic Oligonucleosome Model", Biophys. J. 91: 133--150 (2006).

G. Arya and T. Schlick, ``Role of Histone Tails in Chromatin Folding Revealed by a Mesoscopic Oligonucleosome Model", Proc. Natl. Acad. Sci. 103: 16236--16241 (2006).

G. Arya and T. Schlick, ``Efficient Global Biopolymer Sampling With End-Transfer Configurational Bias Monte Carlo", {\em J. Chem. Phys.} {\bf 126} 044107 (2007).