DNA methylation represents an important layer of epigenetic regulation on the activity of the human genome. It is well known that there is a tremendous amount of genetic variation among human individuals and populations. Such genetic variation leads to the variation of gene expression among different individuals for the same cell types or tissues. Accumulating evidence suggests that the epigenome, including methylome, also varies from one individual to another. Such variation is believed to play functional roles in the individual variation of a variety of phenotypes, including many human diseases. Yet the detailed mechanisms and the extent to which the epigenome is individualized by the ensemble of genetic polymorphisms remains barely investigated. We will comprehensively characterize the effects of genetic polymorphisms on the individual human methylomes. The ultimate goal of this study is to understand how DNA methylation is organized along single human chromosomes, how do such local or long-range organizations relate to the functions, and how do genetic variations affect the functional organization of DNA methylation.
The specific aims are: (1) Experimentally construction of fully phased diploid human genomes, which will serve as a chassis to connect short and long range cis-regulators of DNA methylation, and to link methylation to the binding of protein cis-regulators as well as gene expression. (2) Mapping cis-regulatory variants for DNA methylation by integrating mQTL associative mapping with allele-specific methylation analysis. This proposed study will produce a method for constructing phased diploid methylome and an analytic framework for studying long-range genetic regulation of the DNA methylome. We will identify a list of cis-regulatory variants in the HapMap samples used in this study. The experimental and analytical framework will be applicable to the study of the genetic effects on a variety of other epigenetic modifications.

Public Health Relevance

Epigenetic processes modulate the packaging and function of the human genome in normal developmental processes and in many pathologic states, including human cancers and other common diseases. Disease susceptibility is modulated by both genetic and environmental factors through epigenetic changes. Investigating the effects of genetic variants on and DNA methylome will help elucidating the relative contributions of gene and environment to human diseases, and enabling the identification of more accurate biomarkers for disease prognosis and diagnosis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Krasnewich, Donna M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Engineering (All Types)
Schools of Arts and Sciences
La Jolla
United States
Zip Code
Plongthongkum, Nongluk; van Eijk, Kristel R; de Jong, Simone et al. (2014) Characterization of genome-methylome interactions in 22 nuclear pedigrees. PLoS One 9:e99313
Plongthongkum, Nongluk; Diep, Dinh H; Zhang, Kun (2014) Advances in the profiling of DNA modifications: cytosine methylation and beyond. Nat Rev Genet 15:647-61
Gu, Ying; Liu, Guang-Hui; Plongthongkum, Nongluk et al. (2014) Global DNA methylation and transcriptional analyses of human ESC-derived cardiomyocytes. Protein Cell 5:59-68
Shen, Li; Wu, Hao; Diep, Dinh et al. (2013) Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics. Cell 153:692-706
Lee, Ho Suk; Chu, Wai Keung; Zhang, Kun et al. (2013) Microfluidic devices with permeable polymer barriers for capture and transport of biomolecules and cells. Lab Chip 13:3389-97
Yamaguchi, Shinpei; Hong, Kwonho; Liu, Rui et al. (2013) Dynamics of 5-methylcytosine and 5-hydroxymethylcytosine during germ cell reprogramming. Cell Res 23:329-39
Diep, Dinh; Plongthongkum, Nongluk; Gore, Athurva et al. (2012) Library-free methylation sequencing with bisulfite padlock probes. Nat Methods 9:270-2