Biological and medical implications of discordance in CpG methylation

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.

Department dc:contributor.department

Harvard--MIT Program in Health Sciences and Technology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2017

Author dc:creator

• Clement, Mark Kendell

Advisor dc:contributor.advisor

• Alexander Meissner.

• Harvard--MIT Program in Health Sciences and Technology.

Statement dc:rights

• 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.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/108956

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/108956