title: Pervasive polymorphic imprinted methylation in the human placenta.
abstract: The maternal and paternal copies of the genome are both required for mammalian development, and this is primarily due to imprinted genes, those that are monoallelically expressed based on parent-of-origin. Typically, this pattern of expression is regulated by differentially methylated regions (DMRs) that are established in the germline and maintained after fertilization. There are a large number of germline DMRs that have not yet been associated with imprinting, and their function in development is unknown. In this study, we developed a genome-wide approach to identify novel imprinted DMRs in the human placenta and investigated the dynamics of these imprinted DMRs during development in somatic and extraembryonic tissues. DNA methylation was evaluated using the Illumina HumanMethylation450 array in 134 human tissue samples, publicly available reduced representation bisulfite sequencing in the human embryo and germ cells, and targeted bisulfite sequencing in term placentas. Forty-three known and 101 novel imprinted DMRs were identified in the human placenta by comparing methylation between diandric and digynic triploid conceptions in addition to female and male gametes. Seventy-two novel DMRs showed a pattern consistent with placental-specific imprinting, and this monoallelic methylation was entirely maternal in origin. Strikingly, these DMRs exhibited polymorphic imprinted methylation between placental samples. These data suggest that imprinting in human development is far more extensive and dynamic than previously reported and that the placenta preferentially maintains maternal germline-derived DNA methylation.
authors.affiliation: Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom;
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Hanna
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada; Child & Family Research Institute, Vancouver, British Columbia V5Z 4H4, Canada;
authors.forename: Maria S
authors.initials: MS
authors.lastname: Peñaherrera
authors.affiliation: Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, United Kingdom; Bioinformatics Group, Babraham Institute, Cambridge CB22 3AT, United Kingdom;
authors.forename: Heba
authors.initials: H
authors.lastname: Saadeh
authors.affiliation: Bioinformatics Group, Babraham Institute, Cambridge CB22 3AT, United Kingdom;
authors.forename: Simon
authors.initials: S
authors.lastname: Andrews
authors.affiliation: Department of Pathology, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Deborah E
authors.initials: DE
authors.lastname: McFadden
authors.affiliation: Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom;
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelsey
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada; Child & Family Research Institute, Vancouver, British Columbia V5Z 4H4, Canada;
authors.forename: Wendy P
authors.initials: WP
authors.lastname: Robinson
mesh_terms: D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D010920:Placenta / Q000502:physiology*; D011110:Polymorphism, Genetic; D011247:Pregnancy; D017422:Sequence Analysis, DNA