Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of the human imprintome and suggests a germline methylation independent establishment of imprinting
- Franck Court1,
- Chiharu Tayama2,
- Valeria Romanelli1,
- Alex Martin Trujillo1,
- Isabel Iglesias-Platas3,
- Kohji Okamura2,
- Naoko Sugahara2,
- Carlos Simón4,
- Harry Moore5,
- Julie V Harness6,
- Hans Keirstead6,
- Jose Vicente Sanchez-Mut1,
- Elsuke Kaneki7,
- Pablo Lapunzina8,
- Hidenobu Soejima9,
- Norio Wake7,
- Manel Esteller1,
- Tsutomu Ogata10,
- Kenichiro Hata2,
- Kazuhiko Nakabayashi2 and
- David Monk1,11
- 1 PEBC-IDIBELL;
- 2 National Research Institute for Child Health and Development, Tokyo, Japan;
- 3 Hospital Sant Joan de Déu, Barcelona;
- 4 Universidad de Valencia;
- 5 University of Sheffield;
- 6 University of California, Irvine;
- 7 Kyushu University;
- 8 Hospital La Paz, Madrid;
- 9 Saga University;
- 10 Hamamatsu University School of Medicine
- ↵* Corresponding author; email: dmonk{at}idibell.cat
Abstract
Differential methylation between the two alleles of a gene has been observed at 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 bisulphite 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 identifying 21 novel loci harbouring 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 to identifying primary DMRs and reveal the extent of reprograming during pre-implantation 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.
- Received August 9, 2013.
- Accepted December 26, 2013.
- Published by Cold Spring Harbor Laboratory Press
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