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Dissertation/Thesis Abstract

Analysis of DNA Structure in Nucleosomes
by Shiffeldrim, Nahum, Ph.D., New York University, 2011, 189; 3466965
Abstract (Summary)

The DNA of eukaryotic organisms is packaged into a macromolecular structure, called chromatin. The basic repeating element of chromatin is the nucleosome. Nucleosome positioning along chromosomal DNA is significant in many biological processes such as transcription, replication, DNA repair, and gene regulation. It is well established that nucleosome affinity to DNA is sequence-dependent. Thus, many research endeavors focus on DNA sequence and physical properties in relation to nucleosome affinity. Nucleosome affinity and positioning on DNA differ in vivo and in vitro. In the cell, factors such as DNA binding proteins, chromatin modelers, transcription factors and histone modifying enzymes are at play and contribute to nucleosome binding affinity. However, in vitro, the sequence-dependent nucleosome positioning on DNA is governed by the binding free-energy. Paramount to computation of the sequence-dependent free-energy of DNA deformation is the nucleosomal geometric structure on which a DNA fragment is threaded on. We term this geometric structure - nucleosomal ‘target structure’. The choices of target structure and elastic parameters specify the sequence-dependence of the computed affinity.

The main problem addressed in this study is the proper choice of nucleosome target structure. We evaluate three target structures: Richmond 1kx5 as an illustration of X-ray resolved target structure and two novel target structures: (i) Uniform regular Helix, with sinusoidal Tilt, Roll angles and constant Twist. (ii) A structure we term Optimized, that is obtained by fixing histone-DNA contact positions of 1kx5 and relaxing DNA segments in-between. We assess the target structures via three approaches: (i) Free-Energy Variance - We analyze free-energy variances computed using the target structures and determine which falls closest to the variance of free-energy measurements. (ii) Correlation Maps - We compare experimental and calculated free-energy values indirectly, using correlation between free-energy values and dinucleotide composition of DNA sequences, on plots we term correlation maps. (iii) Positioning Distribution - We utilize nucleosome positioning distributions from footprinting experiments and compare with computed positioning distribution. We illustrate that overall the Helix target structure is the 'best' fitted to be used in computational models.

Indexing (document details)
Advisor: Vologodskii, Alexander
Commitee: Broyde, Suse, Kallenbach, Neville, Seeman, Nadrian, Tuckerman, Mark
School: New York University
Department: Chemistry
School Location: United States -- New York
Source: DAI-B 72/10, Dissertation Abstracts International
Subjects: Molecular biology, Biophysics
Keywords: DNA structure, Free energy, Nucleosomes, Target structure
Publication Number: 3466965
ISBN: 978-1-124-80874-1
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