Understanding how DNA methylation patterns at enhancers record cellular histories
Scott, Timothy Jee Suk
0000-0002-9454-5700
:
2023-11-17
Abstract
DNA methylation is an epigenetic modification that is essential for proper multi-lineage cellular differentiation, though the connection between patterned regions of hypomethylation and phenotype is poorly understood. Over 80% of CpG sites in the genome are methylated, while continuous genomic regions featuring low methylation levels form hypomethylated regions (HMRs). While promoter HMRs are largely consistent across cell types and cell states, subsets of non-coding HMRs are cell-specific and enriched for tissue specific regulatory elements. Our objective was to better understand the implications of patterns of non-coding HMRs both within and between cell types. In this thesis, we systematically dissect HMR patterns across human cell types and tissues representing a diversity of developmental stages, including embryonic, fetal, and adult tissues. Unsupervised hierarchical clustering applied to the methylomes across 11 cell types and tissues, representing >100,000 HMRs, revealed cluster groups that define distinct developmental stages, cell lineages, and individual cell types. Tracking HMRs through pseudo time course representing the hematopoietic lineage revealed that most HMRs (~ 70-75%) in differentiated cells are established at earlier developmental stages and accumulate through cell specification, suggesting a model of hierarchical developmental establishment. HMRs acquired through differentiation frequently (~ 35%) establish near existing HMRs (≤ 6kb), resulting in the formation of HMR clusters associated with stronger enhancer activity. We employed a SNP-based partitioned heritability analysis using GWAS summary statistics across diverse traits and clinical lab values. This analysis indicated that HMRs enrich for cell-relevant trait heritability, increasing with both sequential developmental specificity and HMR clustering. Moreover, cell-specific HMRs enrich for heritability for cell-relevant traits at levels above other enhancer annotations. Our analyses emphasize the power of HMR subsets to predict cell phenotypes; they also highlight DNA methylation as a unique epigenetic mark that provides genetically distinct records of a cell’s history through development.