title: An expression microarray approach for the identification of metastable epialleles in the mouse genome.
abstract: Genetic loci displaying environmentally responsive epigenetic marks, termed metastable epialleles, offer a solution to the paradox presented by genetically identical yet phenotypically distinct individuals. The murine viable yellow agouti (A (vy) ) metastable epiallele exhibits stochastic DNA methylation and histone modifications associated with coat color variation in isogenic individuals. The distribution of A (vy)  variable expressivity shifts following maternal nutritional and environmental exposures. To characterize additional murine metastable epialleles, we utilized genome-wide expression arrays (N = 10 male individuals, 3 tissues per individual) and identified candidates displaying large variability in gene expression among individuals (Vi = inter-individual variance), concomitant with a low variability in gene expression across tissues from the three germ layers (Vt = inter-tissue variance), two features characteristic of the A (vy)  metastable epiallele. The CpG island in the promoter of Dnajb1 and two contraoriented ERV class II repeats in Glcci1 were validated to display underlying stochasticity in methylation patterns common to metastable epialleles. Furthermore, liver DNA methylation in mice exposed in utero to 50 mg bisphenol A (BPA)/kg diet (N = 91) or a control diet (N = 79) confirmed environmental lability at validated candidate genes. Significant effects of exposure on mean CpG methylation were observed at the Glcci1 Repeat 1 locus (p < 0.0001). Significant effects of BPA also were observed at the first and fifth CpG sites studied in Glcci1 Repeat 2 (p < 0.0001 and p = 0.004, respectively). BPA did not affect methylation in the promoter of Dnajb1 (p = 0.59). The characterization of metastable epialleles in humans is crucial for the development of novel screening and therapeutic targets for human disease prevention.
authors.affiliation: Department of Environmental Health Sciences; University of Michigan, Ann Arbor, MI, USA.
authors.forename: Caren
authors.initials: C
authors.lastname: Weinhouse
authors.forename: Olivia S
authors.initials: OS
authors.lastname: Anderson
authors.forename: Tamara R
authors.initials: TR
authors.lastname: Jones
authors.forename: Jung
authors.initials: J
authors.lastname: Kim
authors.forename: Shayna A
authors.initials: SA
authors.lastname: Liberman
authors.forename: Muna S
authors.initials: MS
authors.lastname: Nahar
authors.forename: Laura S
authors.initials: LS
authors.lastname: Rozek
authors.forename: Randy L
authors.initials: RL
authors.lastname: Jirtle
authors.forename: Dana C
authors.initials: DC
authors.lastname: Dolinoy
mesh_terms: D000483:Alleles; D000818:Animals; D001559:Benzhydryl Compounds; D001921:Brain / Q000166:cytology / Q000187:drug effects; D018899:CpG Islands; D019175:DNA Methylation; D004032:Diet; D056426:Genetic Loci; D016678:Genome; D042822:Genomic Instability; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics*; D007668:Kidney / Q000737:chemistry / Q000187:drug effects; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010636:Phenols / Q000494:pharmacology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics; D013269:Stochastic Processes; D020079:Terminal Repeat Sequences; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D050956:HSP40 Heat-Shock Proteins; D010636:Phenols; D011965:Receptors, Glucocorticoid; C494641:Dnajb1 protein, mouse; C568746:glucocorticoid-induced transcript 1 protein, mouse; C006780:bisphenol A; D000098826:Bisphenol A Compounds