Biophysical Models of Gene Regulation

Organizer: Harmen Bussemaker, Columbia University

Speakers: Tamar Schlick, Courant Institute, New York University; Alexandre Morozov, The Rockefeller University; Ye Ding, Wadsworth Center

The Computational Biology and Bioinformatics Discussion Group brings together diverse institutions and communities to share new and relevant information at the frontiers of the interrelated fields of bioinformatics and computational biology. Recent topics have included "Benchmarking and Improving the Accuracy of Comparative Modeling of Protein Structures," "Integrated Statistical Modeling of Gene Expression Data," and "Estimating SNP Haplotype Frequencies from DNA Pools."

Abstracts

Chromatin Modeling and Simulation: A Tale of Histone Tails
Tamar Schlick, PhD
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 addition of linker histones, the chromatin fiber condenses 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.
Coauthors: Qing Zhang and Gaurav Arya

Biophysical Models of Chromatin Structure and Its Effect on Gene Regulation
Alexandre Morozov, PhD
The Rockefeller University

Regulation of gene transcription in eukaryotes is strongly affected by the chromatin: DNA packaged into nucleosomes is not as readily accessible to transcription factors as naked DNA. Nucleosome positions in vivo are determined by both the free energy of nucleosome formation (DNA sequences tested in the lab exhibit more than a thousand-fold range of binding affinities), and by the dynamic competition of histones with other DNA binding proteins for genomic sequence.

We have developed a DNA mechanics-based model for predicting free energies of nucleosome formation (DNABEND), and used it to compute nucleosome positions in the Saccharomyces cerevisiae genome. Our model accurately reproduces in vitro free energy measurements of nucleosome formation, and provides a simple mechanistic explanation for periodic sequence patterns observed in nucleosome positioning sequences. Genome-wide predictions of nucleosome occupanci