DescriptionEukaryotes must pack their DNA into the nucleus tightly, yet accessibly. To accomplish this, the nucleus contains special proteins called histones. Histones bind together to form an octamer, and DNA will wrap around the octamer to form a DNA-protein complex called a nucleosome. Nuclesomes are the primary structure of chromatin, which is the assemblage of DNA and proteins that organizes and stores the genome. 75%-90% of the genome is wound into nucleosomes, yet nucleosomes in the wrong place can block the binding of critical proteins including RNA polymerase: nucleosomes must be kept in their proper locations if the cell is to thrive. Therefore, the cell must regulate the positions of its nucleosomes. How does it accomplish this? Experiments that map the locations of nucleosomes reveal that these locations have a variety of sequence signals in common. That is, nucleosomes are more likely to be form from some kinds of DNA sequences than others. This dissertation addresses the sequence specificity of nucleosome formation. We shall seek answers to questions such as the following: What is the causal role of DNA sequence composition in determining nucleosome positions in vivo? If histones prefer some sequences to others, can we predict which sequences are preferable? Can we quantify the degree of preference? How do intrinsic preferences stack up against the many forces operating in the crowded cell nucleus? To address these and related questions, we have investigated genome-wide nucleosome maps produced by the recently established technology known as Next Generation Sequencing – the first such maps became available less than a decade ago. We have developed a flexible model using the formalism of statistical mechanics on a 1-D lattice to model the binding of histones to DNA. Chapter 2 develops this formalism. In Chapter 3, we shall develop a biophysical model of sequence specificity, applying it to maps of nucleosomes in vitro and in vivo from baker’s yeast, otherwise known as S. cerevisiae. Chapter 4 investi- gates the role of in vivo factors in determining chromatin organization in the nematode C. elegans, where our model suggests that effects occurring on the scale of single nucleosomes are responsible for reorganization of chromatin on a length scale several orders of magnitude greater.