Elucidating the organization of genetic networks and establishing how they contribute to cellular and organismal phenotypes remain to be a grand challenge in our genomic era. Drug response and gene expression are complex phenotypes that are controlled by various genetic and non-genetic factors. Developing genome-based approaches to prediction of drug response could potentially be used in individualized medicine to maximize benefits and minimize harms. A more comprehensive and better characterization of the genetic, epigenetic factors determining complex phenotypes such as drug response, therefore, may significantly benefit the heath of our citizens and provide development opportunities for our biomedical industry. Taking advantage of the rich genetic variation data (e.g., genotypes of ~3.1 million single nucleotide polymorphisms, SNPs) on the International HapMap Project samples, a panel of human lymphoblastoid cell lines (LCLs) derived from apparently healthy individuals, the Dolan (Co-PI of this proposal) Laboratory has pioneered using the LCL model system in pharmacogenomic discovery by integrating genetic and phenotypic data on these samples. Since DNA methylation at the CpG sites of gene promoter regions is a crucial mechanism of gene expression regulation, expanding the current whole genome genetic (e.g., SNP genotypes) and phenotypic data (e.g., mRNA and microRNA expression) on these samples to include DNA methylation may provide novel and critical insights into the underlying mechanism of individual drug response and expression regulation, and reflect a significantly new direction for pharmacogenomic and gene expression studies. We therefore propose to use the NimbleGen 2.1M Deluxe Promoter Array and the MeDIP (methylated DNA immunoprecipitation) assay to profile the natural variation in DNA methylation status at all known promoter regions in 60 unrelated cell lines from the HapMap CEU (derived from Caucasian residents from Utah, USA) samples of Northern and Western European ancestry. The relationships across SNP genotypes, promoter DNA methylation status, gene expression and drug response will be investigated systematically to evaluate the contribution of epigenetics (specifically, DNA methylation) and genetics (specifically, SNPs) to the cytotoxicities of 12 anticancer drugs. Since gene expression is of broad interest to the entire biomedical research community, the primary individual-level DNA methylation data and the methylation-associated signatures for both gene expression and drug response will be put in public domain as a web-based database for easy use and re-analysis. Upon completion, this exploratory project will significantly enhance scientific knowledge in the broad fields of genomics and pharmacogenomics. Finally, the multi-disciplinary nature of our investigative team and the complementary expertise of PIs enhance our ability to conduct the proposed project successfully.

Public Health Relevance

We are committed to the development of genome-based approaches to prediction of drug response variation among patients. This project will provide results from association studies between drug response and DNA methylation, a crucial mechanism of gene regulation, for a variety of anticancer drugs. This proposed project will allow better characterization of the genetic, epigenetic factors determining complex health-related traits such as drug response and facilitate the realization of personalized medical care.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Volpi, Simona
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois at Chicago
Schools of Medicine
United States
Zip Code
Szilágyi, Keely L; Liu, Cong; Zhang, Xu et al. (2017) Epigenetic contribution of the myosin light chain kinase gene to the risk for acute respiratory distress syndrome. Transl Res 180:12-21
Zhou, Qiyuan; Dai, Jingbo; Chen, Tianji et al. (2017) Downregulation of PKC?/Pard3/Pard6b is responsible for lung adenocarcinoma cell EMT and invasion. Cell Signal 38:49-59
Morrison, Gladys; Liu, Cong; Wing, Claudia et al. (2016) Evaluation of inter-batch differences in stem-cell derived neurons. Stem Cell Res 16:140-8
Zhang, Xu; Zhang, Wei (2016) Transcript Isoform Variation Associated with Cytosine Modification in Human Lymphoblastoid Cell Lines. Genetics 203:985-95
Tang, Ke; Zhang, Wei (2016) Transcriptional similarity in couples reveals the impact of shared environment and lifestyle on gene regulation through modified cytosines. PeerJ 4:e2123
Zhang, Zhou; Zheng, Yinan; Zhang, Xu et al. (2016) Linking short tandem repeat polymorphisms with cytosine modifications in human lymphoblastoid cell lines. Hum Genet 135:223-32
Moen, Erika L; Litwin, Edward; Arnovitz, Stephen et al. (2015) Characterization of CpG sites that escape methylation on the inactive human X-chromosome. Epigenetics 10:810-8
Liu, Cong; Xu, Junhui; Chen, Yahong et al. (2015) Characterization of genome-wide H3K27ac profiles reveals a distinct PM2.5-associated histone modification signature. Environ Health 14:65
Zhang, Wei; Gamazon, Eric R; Zhang, Xu et al. (2015) SCAN database: facilitating integrative analyses of cytosine modification and expression QTL. Database (Oxford) 2015:
Zhang, Xu; Moen, Erika L; Liu, Cong et al. (2014) Linking the genetic architecture of cytosine modifications with human complex traits. Hum Mol Genet 23:5893-905

Showing the most recent 10 out of 23 publications