Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment

Differential methylation between the two alleles of a gene has been observed in imprinted regions, where the methylation of one allele occurs on a parent-of-origin basis, the inactive X-chromosome in females, and at those loci whose methylation is driven by genetic variants. We have extensively characterized imprinted methylation in a substantial range of normal human tissues, reciprocal genome-wide uniparental disomies, and hydatidiform moles, using a combination of whole-genome bisulfite sequencing and high-density methylation microarrays. This approach allowed us to define methylation profiles at known imprinted domains at base-pair resolution, as well as to identify 21 novel loci harboring parent-of-origin methylation, 15 of which are restricted to the placenta. We observe that the extent of imprinted differentially methylated regions (DMRs) is extremely similar between tissues, with the exception of the placenta. This extra-embryonic tissue often adopts a different methylation profile compared to somatic tissues. Further, we profiled all imprinted DMRs in sperm and embryonic stem cells derived from parthenogenetically activated oocytes, individual blastomeres, and blastocysts, in order to identify primary DMRs and reveal the extent of reprogramming during preimplantation development. Intriguingly, we find that in contrast to ubiquitous imprints, the majority of placenta-specific imprinted DMRs are unmethylated in sperm and all human embryonic stem cells. Therefore, placental-specific imprinting provides evidence for an inheritable epigenetic state that is independent of DNA methylation and the existence of a novel imprinting mechanism at these loci.

[1]  Yen Ching Lim,et al.  DNMT1 and AIM1 Imprinting in human placenta revealed through a genome-wide screen for allele-specific DNA methylation , 2013, BMC Genomics.

[2]  Yen Ching Lim,et al.  DNMT1 and AIM1 Imprinting in human placenta revealed through a genome-wide screen for allele-specific DNA methylation , 2013, BMC Genomics.

[3]  G. Grimaldi,et al.  Genetic and epigenetic mutations affect the DNA binding capability of human ZFP57 in transient neonatal diabetes type 1 , 2013, FEBS letters.

[4]  T. Kono,et al.  Epigenetic and transcriptional features of the novel human imprinted lncRNA GPR1AS suggest it is a functional ortholog to mouse Zdbf2linc , 2013, Epigenetics.

[5]  R. Weksberg,et al.  Molecular Findings in Beckwith–Wiedemann Syndrome , 2013, American journal of medical genetics. Part C, Seminars in medical genetics.

[6]  Wendy P Robinson,et al.  The human placenta methylome , 2013, Proceedings of the National Academy of Sciences.

[7]  A. Guillaumet-Adkins,et al.  Imprinting at the PLAGL1 domain is contained within a 70-kb CTCF/cohesin-mediated non-allelic chromatin loop , 2013, Nucleic acids research.

[8]  V. Rakyan,et al.  Protection against De Novo Methylation Is Instrumental in Maintaining Parent-of-Origin Methylation Inherited from the Gametes , 2012, Molecular cell.

[9]  D. Geschwind,et al.  Divergent whole-genome methylation maps of human and chimpanzee brains reveal epigenetic basis of human regulatory evolution. , 2012, American journal of human genetics.

[10]  Amélie C Pinard,et al.  A genome-wide approach reveals novel imprinted genes expressed in the human placenta , 2012, Epigenetics.

[11]  Alfonso Valencia,et al.  Distinct DNA methylomes of newborns and centenarians , 2012, Proceedings of the National Academy of Sciences.

[12]  M. Bartolomei,et al.  Genomic imprinting: recognition and marking of imprinted loci. , 2012, Current opinion in genetics & development.

[13]  Zachary D. Smith,et al.  A unique regulatory phase of DNA methylation in the early mammalian embryo , 2012, Nature.

[14]  B. Ren,et al.  Base-Resolution Analyses of Sequence and Parent-of-Origin Dependent DNA Methylation in the Mouse Genome , 2012, Cell.

[15]  K. Nakayama,et al.  Re-investigation and RNA sequencing-based identification of genes with placenta-specific imprinted expression. , 2012, Human molecular genetics.

[16]  Yutaka Suzuki,et al.  Contribution of Intragenic DNA Methylation in Mouse Gametic DNA Methylomes to Establish Oocyte-Specific Heritable Marks , 2012, PLoS genetics.

[17]  D. Trono,et al.  In Embryonic Stem Cells, ZFP57/KAP1 Recognize a Methylated Hexanucleotide to Affect Chromatin and DNA Methylation of Imprinting Control Regions , 2011, Molecular cell.

[18]  W. Richard McCombie,et al.  Sperm Methylation Profiles Reveal Features of Epigenetic Inheritance and Evolution in Primates , 2011, Cell.

[19]  H. Aburatani,et al.  Methylation screening of reciprocal genome-wide UPDs identifies novel human-specific imprinted genes. , 2011, Human molecular genetics.

[20]  P. Lapunzina,et al.  The consequences of uniparental disomy and copy number neutral loss‐of‐heterozygosity during human development and cancer , 2011, Biology of the cell.

[21]  S. Andrews,et al.  Dynamic CpG island methylation landscape in oocytes and preimplantation embryos , 2011, Nature Genetics.

[22]  Julie V. Harness,et al.  Equivalence of Conventionally-Derived and Parthenote-Derived Human Embryonic Stem Cells , 2011, PloS one.

[23]  M. Fraga,et al.  Constitutional mosaic genome-wide uniparental disomy due to diploidisation: an unusual cancer-predisposing mechanism , 2010, Journal of Medical Genetics.

[24]  A. Sharp,et al.  Methylation profiling in individuals with uniparental disomy identifies novel differentially methylated regions on chromosome 15. , 2010, Genome research.

[25]  D. Mackay,et al.  Transient neonatal diabetes mellitus type 1 , 2010, American journal of medical genetics. Part C, Seminars in medical genetics.

[26]  T. Eggermann.  Russell–Silver syndrome , 2010, American journal of medical genetics. Part C, Seminars in medical genetics.

[27]  K. Buiting.  Prader–Willi syndrome and Angelman syndrome , 2010, American journal of medical genetics. Part C, Seminars in medical genetics.

[28]  G. Kelsey.  Imprinting on chromosome 20: Tissue‐specific imprinting and imprinting mutations in the GNAS locus , 2010, American journal of medical genetics. Part C, Seminars in medical genetics.

[29]  S. Luo,et al.  High-Resolution Analysis of Parent-of-Origin Allelic Expression in the Mouse Brain , 2010, Science.

[30]  K. Yamazawa,et al.  Parthenogenetic chimaerism/mosaicism with a Silver-Russell syndrome-like phenotype , 2010, Journal of Medical Genetics.

[31]  J. Cavaille,et al.  The primate-specific microRNA gene cluster (C19MC) is imprinted in the placenta. , 2010, Human molecular genetics.

[32]  D. Monk.  Deciphering the cancer imprintome. , 2010, Briefings in functional genomics.

[33]  W. Cooper,et al.  How genome-wide approaches can be used to unravel the remaining secrets of the imprintome. , 2010, Briefings in functional genomics.

[34]  Albert Jeltsch,et al.  The Dnmt3a PWWP Domain Reads Histone 3 Lysine 36 Trimethylation and Guides DNA Methylation* , 2010, The Journal of Biological Chemistry.

[35]  A. Green,et al.  The IG-DMR and the MEG3-DMR at Human Chromosome 14q32.2: Hierarchical Interaction and Distinct Functional Properties as Imprinting Control Centers , 2010, PLoS genetics.

[36]  Robert S. Illingworth,et al.  CpG islands influence chromatin structure via the CpG-binding protein Cfp1 , 2010, Nature.

[37]  N. Yaegashi,et al.  A tripartite paternally methylated region within the Gpr1-Zdbf2 imprinted domain on mouse chromosome 1 identified by meDIP-on-chip , 2010, Nucleic acids research.

[38]  Albert Jeltsch,et al.  Chromatin methylation activity of Dnmt3a and Dnmt3a/3L is guided by interaction of the ADD domain with the histone H3 tail , 2010, Nucleic acids research.

[39]  Daniel F. Gudbjartsson,et al.  Parental origin of sequence variants associated with complex diseases , 2009, Nature.

[40]  R. Siebert,et al.  The Human Retinoblastoma Gene Is Imprinted , 2009, PLoS genetics.

[41]  Lee E. Edsall,et al.  Human DNA methylomes at base resolution show widespread epigenomic differences , 2009, Nature.

[42]  E. Li,et al.  KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints , 2009, Nature.

[43]  B. Cairns,et al.  Distinctive Chromatin in Human Sperm Packages Genes for Embryo Development , 2009, Nature.

[44]  D. Amor,et al.  A review of known imprinting syndromes and their association with assisted reproduction technologies. , 2008, Human reproduction.

[45]  P. Leder,et al.  A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. , 2008, Developmental cell.

[46]  Reiner Schulz,et al.  Regulation of alternative polyadenylation by genomic imprinting. , 2008, Genes & development.

[47]  A. Ferguson-Smith,et al.  Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes , 2008, Nature Genetics.

[48]  QingYun Mai,et al.  Derivation of human embryonic stem cell lines from parthenogenetic blastocysts , 2007, Cell Research.

[49]  I. Liebaers,et al.  Methylation analysis of the intergenic differentially methylated region of DLK1-GTL2 in human , 2007, European Journal of Human Genetics.

[50]  S. Apostolidou,et al.  Limited evolutionary conservation of imprinting in the human placenta. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[51]  Yi Zhang,et al.  Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes , 2004, Nature Genetics.

[52]  C. Fuke,et al.  Age Related Changes in 5‐methylcytosine Content in Human Peripheral Leukocytes and Placentas: an HPLC‐based Study , 2004, Annals of human genetics.

[53]  A. Grinberg,et al.  The H19 Differentially Methylated Region Marks the Parental Origin of a Heterologous Locus without Gametic DNA Methylation , 2004, Molecular and Cellular Biology.

[54]  M. Bartolomei,et al.  Transgenic RNAi Reveals Essential Function for CTCF in H19 Gene Imprinting , 2004, Science.

[55]  G. Kelsey,et al.  Epigenetic Properties and Identification of an Imprint Mark in the Nesp-Gnasxl Domain of the Mouse Gnas Imprinted Locus , 2003, Molecular and Cellular Biology.

[56]  W. Reik,et al.  Epigenetic modifications in an imprinting cluster are controlled by a hierarchy of DMRs suggesting long-range chromatin interactions. , 2003, Human molecular genetics.

[57]  E. Li,et al.  Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. , 2002, Development.

[58]  T. Bestor,et al.  Dnmt3L and the Establishment of Maternal Genomic Imprints , 2001, Science.

[59]  J. Walter,et al.  Maternal methylation imprints on human chromosome 15 are established during or after fertilization , 2001, Nature Genetics.

[60]  G. Kelsey,et al.  Identification of imprinted loci by methylation-sensitive representational difference analysis: application to mouse distal chromosome 2. , 1999, Genomics.

[61]  D. Davidson.  Hormone replacement therapy. , 1990, American family physician.

[62]  M. Ehrlich,et al.  Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells. , 1982, Nucleic acids research.

[63]  Nan Faion T. Wu,et al.  The Beckwith-Wiedemann Syndrome , 1974, Clinical pediatrics.

[64]  R. Yuen,et al.  Genome-wide mapping of imprinted differentially methylated regions by DNA methylation profiling of human placentas from triploidies , 2011 .

[65]  Satoshi Tanaka,et al.  PGC7/Stella protects against DNA demethylation in early embryogenesis , 2007, Nature Cell Biology.

[66]  Gavin Kelsey,et al.  Resourceful imprinting : Fertility , 2004 .

[67]  Wolf Reik,et al.  Resourceful imprinting , 2004, Nature.

[68]  J. A. Lozano Rodríguez,et al.  [Transient neonatal diabetes mellitus]. , 1998, Anales espanoles de pediatria.

[69]  V. Chapman,et al.  Identification of an imprinted U2af binding protein related sequence on mouse chromosome 11 using the RLGS method , 1994, Nature Genetics.

[70]  S. Andrews,et al.  Dynamic stage-specific changes in imprinted differentially methylated regions during early mammalian development and prevalence of non-CpG methylation in oocytes , 2022 .