Professor Jon Widom
Chemistry Department
Northwestern University
Evanston, Illinois

Wednesday, September 27, 2006
4:30 pm (CT)
Beckman Institute Auditorium

Abstract

The genomic DNA of eukaryotes is tightly wrapped into chromosomes through a hierarchical series of folding steps. In the lowest level of compaction, short stretches of DNA are wrapped around small octameric protein spools, forming structures known as nucleosomes. The structure of the nucleosome occludes most of the wrapped DNA from interaction with the regulatory proteins and enzymes that must act on it. I will discuss studies using enzymatic and fluorescence probes that show nucleosomes to spontaneously undergo rapid, large-scale, conformational fluctuations that facilitate the invasion of nucleosomes by gene regulatory proteins. I will then discuss studies on DNA sequence motifs that bias where nucleosomes are placed along the DNA and control the stabilities of nucleosomes. I will summarize our progress identifying such nucleosome positioning DNA sequences, and our current understanding of how such sequences function to attract and stabilize nucleosomes. We have used this information in a novel computational approach to construct and experimentally validate a nucleosome-DNA interaction model, and to predict the genome-wide organization of nucleosomes. Our results demonstrate that genomes encode an intrinsic nucleosome organization, and that this intrinsic organization itself can explain ~50% of the in vivo nucleosome positions. This nucleosome positioning code may facilitate specific chromosome functions, including transcription factor binding, transcription initiation, and even remodeling of the nucleosomes themselves.