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Alexander Meissner. Clement, Mark Kendell Harvard--MIT Program in Health Sciences and Technology. Harvard University--MIT Division of Health Sciences and Technology 2017-05-11T19:57:45Z 2017-05-11T19:57:45Z 2017 2017 http://hdl.handle.net/1721.1/108956 986479867 Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2017. Cataloged from PDF version of thesis. Includes bibliographical references (pages 121-160). DNA methylation is an important epigenetic mark that is linked to the regulation of gene expression. It is a critical part of controlling cellular identity and is essential for normal development. DNA methylation is generally studied by comparing methylation levels at individual cytosines or computing region-level averages to identify differential methylation. Here we extended this classic viewpoint by capitalizing on a unique feature of next-generation sequencing, which provides the methylation status of CpGs that are located on the same sequencing read and hence originate from the same DNA molecule. When comparing methylation states of CpGs on the same read, we observed different levels of discordant methylation, defined as molecules where the methylation of neighboring cytosines are not correlated. We quantified the proportion of discordantly methylated reads (PDR) in normal and cancer samples, and found that global PDR levels were elevated in cancer, suggesting widespread epigenetic deregulation. While we have not yet established the mechanistic contribution of this feature, we find that discordant methylation is linked to higher genetic diversity, greater cell-to-cell transcriptional heterogeneity, and adverse clinical outcome in chronic lymphocytic leukemia (CLL). Our analytic approach introduces a novel perspective on utilizing epigenomic sequencing data, which we anticipate will be a valuable tool in understanding the regulation of DNA methylation and its contribution to cellular identity. by Mark Kendell Clement. Ph.D. in Medical Engineering and Medical Physics 160 pages eng Massachusetts Institute of Technology MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. http://dspace.mit.edu/handle/1721.1/7582 Harvard--MIT Program in Health Sciences and Technology. Biological and medical implications of discordance in CpG methylation Biological and medical implications of discordance in C phosphate G methylation Thesis application/pdf false Publication unknown unknown <Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="8b6caab2-cc8e-4b57-9bd0-071b1436f8ea"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Language>eng</Language> <Title>Biological and medical implications of discordance in CpG methylation</Title> <Subtitle>Biological and medical implications of discordance in C phosphate G methylation</Subtitle> <PublishedIn> <Publication> </Publication> </PublishedIn> <PublicationDate>2017</PublicationDate> <Authors> <Author> <DisplayName>Clement, Mark Kendell</DisplayName> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <DisplayName>Massachusetts Institute of Technology</DisplayName> <OrgUnit /> </Publisher> </Publishers> <License>http://dspace.mit.edu/handle/1721.1/7582</License> <Keyword>Harvard--MIT Program in Health Sciences and Technology.</Keyword> <Abstract>DNA methylation is an important epigenetic mark that is linked to the regulation of gene expression. It is a critical part of controlling cellular identity and is essential for normal development. DNA methylation is generally studied by comparing methylation levels at individual cytosines or computing region-level averages to identify differential methylation. Here we extended this classic viewpoint by capitalizing on a unique feature of next-generation sequencing, which provides the methylation status of CpGs that are located on the same sequencing read and hence originate from the same DNA molecule. When comparing methylation states of CpGs on the same read, we observed different levels of discordant methylation, defined as molecules where the methylation of neighboring cytosines are not correlated. We quantified the proportion of discordantly methylated reads (PDR) in normal and cancer samples, and found that global PDR levels were elevated in cancer, suggesting widespread epigenetic deregulation. While we have not yet established the mechanistic contribution of this feature, we find that discordant methylation is linked to higher genetic diversity, greater cell-to-cell transcriptional heterogeneity, and adverse clinical outcome in chronic lymphocytic leukemia (CLL). Our analytic approach introduces a novel perspective on utilizing epigenomic sequencing data, which we anticipate will be a valuable tool in understanding the regulation of DNA methylation and its contribution to cellular identity.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication>