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

Franck Court, Chiharu Tayama, Valeria Romanelli, Alex Martin-Trujillo, Isabel Iglesias-Platas, Kohji Okamura, Naoko Sugahara, Carlos Simón, Harry Moore, Julie V. Harness, Hans Keirstead, Jose Vicente Sanchez-Mut, Eisuke Kaneki, Pablo Lapunzina, Hidenobu Soejima, Norio Wake, Manel Esteller, Tsutomu Ogata, Kenichiro Hata, Kazuhiko NakabayashiDavid Monk

Research output: Contribution to journalArticle

160 Citations (Scopus)

Abstract

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 wholegenome 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.

Original languageEnglish
Pages (from-to)554-569
Number of pages16
JournalGenome Research
Volume24
Issue number4
DOIs
Publication statusPublished - Apr 2014

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DNA Methylation
Methylation
Genome
Placenta
Spermatozoa
Alleles
Uniparental Disomy
Hydatidiform Mole
Blastomeres
X Chromosome
Blastocyst
Embryonic Stem Cells
Epigenomics
Base Pairing
Oocytes
Reference Values
Genes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment. / Court, Franck; Tayama, Chiharu; Romanelli, Valeria; Martin-Trujillo, Alex; Iglesias-Platas, Isabel; Okamura, Kohji; Sugahara, Naoko; Simón, Carlos; Moore, Harry; Harness, Julie V.; Keirstead, Hans; Sanchez-Mut, Jose Vicente; Kaneki, Eisuke; Lapunzina, Pablo; Soejima, Hidenobu; Wake, Norio; Esteller, Manel; Ogata, Tsutomu; Hata, Kenichiro; Nakabayashi, Kazuhiko; Monk, David.

In: Genome Research, Vol. 24, No. 4, 04.2014, p. 554-569.

Research output: Contribution to journalArticle

Court, F, Tayama, C, Romanelli, V, Martin-Trujillo, A, Iglesias-Platas, I, Okamura, K, Sugahara, N, Simón, C, Moore, H, Harness, JV, Keirstead, H, Sanchez-Mut, JV, Kaneki, E, Lapunzina, P, Soejima, H, Wake, N, Esteller, M, Ogata, T, Hata, K, Nakabayashi, K & Monk, D 2014, 'Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment', Genome Research, vol. 24, no. 4, pp. 554-569. https://doi.org/10.1101/gr.164913.113
Court, Franck ; Tayama, Chiharu ; Romanelli, Valeria ; Martin-Trujillo, Alex ; Iglesias-Platas, Isabel ; Okamura, Kohji ; Sugahara, Naoko ; Simón, Carlos ; Moore, Harry ; Harness, Julie V. ; Keirstead, Hans ; Sanchez-Mut, Jose Vicente ; Kaneki, Eisuke ; Lapunzina, Pablo ; Soejima, Hidenobu ; Wake, Norio ; Esteller, Manel ; Ogata, Tsutomu ; Hata, Kenichiro ; Nakabayashi, Kazuhiko ; Monk, David. / Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment. In: Genome Research. 2014 ; Vol. 24, No. 4. pp. 554-569.
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AU - Iglesias-Platas, Isabel

AU - Okamura, Kohji

AU - Sugahara, Naoko

AU - Simón, Carlos

AU - Moore, Harry

AU - Harness, Julie V.

AU - Keirstead, Hans

AU - Sanchez-Mut, Jose Vicente

AU - Kaneki, Eisuke

AU - Lapunzina, Pablo

AU - Soejima, Hidenobu

AU - Wake, Norio

AU - Esteller, Manel

AU - Ogata, Tsutomu

AU - Hata, Kenichiro

AU - Nakabayashi, Kazuhiko

AU - Monk, David

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N2 - 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 wholegenome 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.

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