Computational Modeling And Analysis Of Chromatin Structure

Author : Christopher Cameron
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (122 download)

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Download or read book High-resolution Computational Analysis of Chromatin Architecture and Function written by Christopher Cameron and published by . This book was released on 2019 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Since sequencing the human genome in the early 2000s, researchers have been determined to define the genetic pathways that regulate cellular activity or lead to disease. With the recent advent of Chromosome Conformation Capture (3C) technologies, the ability to observe chromatin’s three-dimensional (3D) structure became a possibility. It quickly became apparent that the genome is not regulated in one-dimension, but in 3D where chromatin loops are formed between an enhancer(s) and promoter to regulate a gene’s transcription. While 3C technology is quite useful, most protocols are limited in their resolution and availability across cell types and genomes. This limited resolution is a common concern for many technologies that study the regulation of genomes, such as Chromatin Immunoprecipitation (ChIP), and typically results from low-coverage sequencing. The objective of this thesis is to develop computational and biochemical methodologies that provide accurate, high-resolution genomic data for deciphering the organization and regulation of genomes. The first contribution in this thesis is Hi-C Interaction Frequency Inference (HIFI), a collection of density estimation algorithms for High-throughput 3C (Hi-C) data. Hi-C is a particularly useful 3C technology that identifies chromatin contacts genome-wide. HIFI allows Hi-C data to be analyzed at the highest possible resolution (restriction fragments) while providing the most accurate estimation of chromatin contact frequency when compared to other techniques in the field. The higher resolution afforded by HIFI has lead to the discovery of a potential role for active promoters and enhancers at the boundaries of Topologically Associating Domains (TADs). Next, we developed machine learning approaches to predict chromatin interaction frequencies from the reference genome sequence alone. While some machine learning work has been done to predict Hi-C data, all these models rely on biochemical input to make their predictions, which makes them impossible to use in cases where this data is unavailable (e.g., computationally inferred ancestral genomes). By limiting model input to features derived from sequence only, their predictions enable us to identify sequence determinants of 3D genome organization. Finally, we present a targeted and affordable ChIP methodology, called ‘Carbon Copy-ChIP’ (2C-ChIP), that continues our foray into high-resolution chromatin assays. 2C-ChIP provides quantifiable measures of bound protein across the genome at a cost that makes it very attractive for studies involving multiple experimental conditions (e.g., drug design). We also describe a computational tool for processing 2C-ChIP products called the Ligation-mediated Amplified, Multiplexed Paired-end Sequence (LAMPS) analysis pipeline.Taken together, the work in this thesis provides new ways to study genome function and organization affordably and at high resolution"--