Using biophysical models to understand eukaryotic chromatin structure and regulation of gene transcription
Speaker: Alexandre Morozov , Rockefeller University
Date: April 25 2007
Time: 11:30AM to 1:00PM
Location: TOC lab 32-G575
Host: Bonnie Berger and Peter Clote, MIT/BC
Contact: Patrice Macaluso, 617-253-3037, macaluso@csail.mit.edu
Relevant URL: Alexandre V. Morozov* and Eric D. Siggia
Center for Studies in Physics and Biology, The Rockefeller University, 1230 York Avenue, New York NY 10021
morozov@edsb.rockefeller.edu
Abstract
Regulation of gene transcription in eukaryotes is strongly affected by the chromatin structure: DNA
packaged into nucleosome core particles is not as readily accessible to transcription factors as naked
DNA. Nucleosome positions in eukaryotic genomes are determined by both the free energy of nucleo-
some 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 factors for regulatory
sequence.
We have developed a DNA mechanics-based model for predicting free energies of nucleosome for-
mation (DNABEND), and used it to predict nucleosome positions in the Saccharomyces cerevisiae
genome. Our model accurately reproduces available in vitro measurements of nucleosome free energies,
and provides a simple mechanistic explanation for periodic sequence patterns observed in nucleosome
positioning sequences. Genome-wide calculations of nucleosome positions reveal intrinsic nucleoso-
mal organization of the yeast genome, and highlight the role of nucleosomes in facilitating in vivo
chromosomal functions. We argue that it is the dynamic competition between nucleosomes and TATA
binding proteins (TBPs) that determines experimentally observed chromatin structure around transcrip-
tion/translation start sites. We also find that the nucleosome-induced cooperativity plays an important
role in differentiating functional transcription factor binding sites (determined with ChIP-on-chip exper-
iments) from the non-functional sites with similar binding energies.
Joint work with Jonathan Widom (Northwestern University) and Eran Segal (Weizmann Institute of
Science).
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