title: Human metastable epiallele candidates link to common disorders.
abstract: Metastable epialleles (MEs) are mammalian genomic loci where epigenetic patterning occurs before gastrulation in a stochastic fashion leading to systematic interindividual variation within one species. Importantly, periconceptual nutritional influences may modulate the establishment of epigenetic changes, such as DNA methylation at MEs. Based on these characteristics, we exploited Infinium HumanMethylation450 BeadChip kits in a 2-tissue parallel screen on peripheral blood leukocyte and colonic mucosal DNA from 10 children without identifiable large intestinal disease. This approach led to the delineation of 1776 CpG sites meeting our criteria for MEs, which associated with 1013 genes. The list of ME candidates exhibited overlaps with recently identified human genes (including CYP2E1 and MGMT, where methylation has been associated with Parkinson disease and glioblastoma, respectively) in which perinatal DNA methylation levels where linked to maternal periconceptual nutrition. One hundred 18 (11.6%) of the ME candidates overlapped with genes where DNA methylation correlated (r > 0.871; p < 0.055) with expression in the colon mucosa of 5 independent control children. Genes involved in homophilic cell adhesion (including cadherin-associated genes) and developmental processes were significantly overrepresented in association with MEs. Additional filtering of gene expression-correlated MEs defined 35 genes, associated with 2 or more CpG sites within a 10 kb genomic region, fulfilling the ME criteria. DNA methylation changes at a number of these genes have been linked to various forms of human disease, including cancers, such as asthma and acute myeloid leukemia (ALOX12), gastric cancer (EBF3), breast cancer (NAV1), colon cancer and acute lymphoid leukemia (KCNK15), Wilms tumor (protocadherin gene cluster; PCDHAs) and colorectal cancer (TCERG1L), suggesting a potential etiologic role for MEs in tumorigenesis and underscoring the possible developmental origins of these malignancies. The presented compendium of ME candidates may accelerate our understanding of the epigenetic origins of common human disorders.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors: R Alan
authors: RA
authors: Harris
authors: Dorottya
authors: D
authors: Nagy-Szakal
authors: Richard
authors: R
authors: Kellermayer
mesh_terms: D001249:Asthma / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D007413:Intestinal Mucosa / Q000502:physiology*; D008869:Microtubule-Associated Proteins; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000378:metabolism; D014430:Twins, Monozygotic / Q000235:genetics
chemical_list: C431132:KCNK15 protein, human; D008869:Microtubule-Associated Proteins; C477056:NAV1 protein, human; D009414:Nerve Growth Factors; D024683:Potassium Channels, Tandem Pore Domain
keywords: DNA methylation; developmental origins; epigenetics; metastable epiallele; nutrition