Epigenetic information involves any alteration that does not cause DNA sequence changes. Common epigenetic alterations include DNA methylation and post-translational modifications of histones. Genomic imprinting and X chromosome inactivation are special cases of epigenetic phenomena in which epigenetic modifications differ between the two parental chromosomes, leading to a preferential expression of one parental allele. To study allelic gene expression globally, we reengineered the assay and analysis of the Affymetrix HuSNP chip so that it measures allele-specific transcript variation. We observed gene expression differences between the two chromosomes within the same individual. The relative expression of specific alleles, however, varied between individuals suggesting a dependence on genomic context. We have observed differences due to haplotypes, chromatin features, and methylation status. These studies from our lab have established that allelic variation in gene expression is common throughout the human genome. In addition our studies suggest that global epigenetic regulation may segregate as a complex trait. To map and identify genes that control epigenetic regulation, we perform genome-wide experiments on gene expression, chromatin immunoprecipitation (ChIP), and DNA methylation using samples from the HapMap project. The genotype and linkage disequilibrium (LD) resource from the HapMap project should expedite our effort to obtain a complete description for the genetic and epigenetic regulatory networks of gene expression. Tumor progression and metastasis is the result of the intersection of susceptibility genes, micro-environmental exposures and somatic mutations. One component of tumor progression and metastasis includes epigenetic silencing of tumor suppressor genes and metastasis suppression genes. To study the potential role of allele-specific DNA methylation in breast cancer etiology and its application in diagnosis and treatment, we initiated experiments to investigate the role of allele-specific DNA methylation in tumor progression and metastasis using Affymetrix SNP chips. We performed allele-specific DNA methylation experiments on primary breast tumors and their matched normal samples. We have identified 8 genes including GPC6, TIMP2, FBN1, SYTL3, DGKH, KCTD10, SH3GL3, and ARID1B that showed significant methylation difference between node positive and negative tumors. Significantly, gene expression level of these genes can also predict survival by Kaplan-Meier analysis.
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