Allele-Specific Chromatin Immunoprecipitation Studies Show Genetic Influence on Chromatin State in Human Genome

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Abstract
Several recent studies have shown a genetic influence on gene expression variation, including variation between the two chromosomes within an individual and variation between individuals at the population level. We hypothesized that genetic inheritance may also affect variation in chromatin states. To test this hypothesis, we analyzed chromatin states in 12 lymphoblastoid cells derived from two Centre d'Etude du Polymorphisme Humain families using an allele-specific chromatin immunoprecipitation (ChIP-on-chip) assay with Affymetrix 10K SNP chip. We performed the allele-specific ChIP-on-chip assays for the 12 lymphoblastoid cells using antibodies targeting at RNA polymerase II and five post-translation modified forms of the histone H3 protein. The use of multiple cell lines from the Centre d'Etude du Polymorphisme Humain families allowed us to evaluate variation of chromatin states across pedigrees. These studies demonstrated that chromatin state clustered by family. Our results support the idea that genetic inheritance can determine the epigenetic state of the chromatin as shown previously in model organisms. To our knowledge, this is the first demonstration in humans that genetics may be an important factor that influences global chromatin state mediated by histone modification, the hallmark of the epigenetic phenomena. Human health and disease are determined by an interaction between genetic background and environmental exposures. Both normal development and disease are mediated by epigenetic regulation of gene expression. The epigenetic regulation causes heritable changes in gene expression, which is not associated with DNA sequence changes. Instead, it is mediated by chemical modification of DNA such as DNA methylation or by protein modifications such as histone acetylation and methylation. Although much has been known about epigenetic inheritance during development, little is known about the influence of the genetic background on epigenetic processes such as histone modifications. In this report the authors studied five histone modifications on a genome-wide level in cells from different families. Global epigenetic states, as measured by these histone modifications, showed a similar pattern for cells derived from the same family. This study demonstrates that genetic inheritance may be an important factor influencing global chromatin states mediated by histone modifications in humans. These observations illustrate the importance of integrating genetic and epigenetic information into studies of human health and complex diseases.