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Article: Global mapping of DNA methylation in mouse promoters reveals epigenetic reprogramming of pluripotency genes

TitleGlobal mapping of DNA methylation in mouse promoters reveals epigenetic reprogramming of pluripotency genes
Authors
Issue Date2008
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosgenetics.org/
Citation
Plos Genetics, 2008, v. 4 n. 6 How to Cite?
AbstractDNA methylation patterns are reprogrammed in primordial germ cells and in preimplantation embryos by demethylation and subsequent de novo methylation. It has been suggested that epigenetic reprogramming may be necessary for the embryonic genome to return to a pluripotent state. We have carried out a genome-wide promoter analysis of DNA methylation in mouse embryonic stem (ES) cells, embryonic germ (EG) cells, sperm, trophoblast stem (TS) cells, and primary embryonic fibroblasts (pMEFs). Global clustering analysis shows that methylation patterns of ES cells, EG cells, and sperm are surprisingly similar, suggesting that while the sperm is a highly specialized cell type, its promoter epigenome is already largely reprogrammed and resembles a pluripotent state. Comparisons between pluripotent tissues and pMEFs reveal that a number of pluripotency related genes, including Nanog, Lefty1 and Tdgf1, as well as the nucleosome remodeller Smarcd1, are hypomethylated in stem cells and hypermethylated in differentiated cells. Differences in promoter methylation are associated with significant differences in transcription levels in more than 60% of genes analysed. Our comparative approach to promoter methylation thus identifies gene candidates for the regulation of pluripotency and epigenetic reprogramming. While the sperm genome is, overall, similarly methylated to that of ES and EG cells, there are some key exceptions, including Nanog and Lefty1, that are highly methylated in sperm. Nanog promoter methylation is erased by active and passive demethylation after fertilisation before expression commences in the morula. In ES cells the normally active Nanog promoter is silenced when targeted by de novo methylation. Our study suggests that reprogramming of promoter methylation is one of the key determinants of the epigenetic regulation of pluripotency genes. Epigenetic reprogramming in the germline prior to fertilisation and the reprogramming of key pluripotency genes in the early embryo is thus crucial for transmission of pluripotency. © 2008 Farthing et al.
Persistent Identifierhttp://hdl.handle.net/10722/148567
ISSN
2014 Impact Factor: 7.528
2015 SCImago Journal Rankings: 6.308
ISI Accession Number ID
Funding AgencyGrant Number
CellCentric
Technology Strategy Board's Collaborative Research and Development programme
BBSRC
MRC
EU NoE
RKN
Funding Information:

This work was funded by CellCentric, the Technology Strategy Board's Collaborative Research and Development programme, BBSRC, MRC, and EU NoE The Epigenome, and by a Croucher Foundation Fellowship to RKN.

References

 

DC FieldValueLanguage
dc.contributor.authorFarthing, CRen_US
dc.contributor.authorFicz, Gen_US
dc.contributor.authorNg, RKen_US
dc.contributor.authorChan, CFen_US
dc.contributor.authorAndrews, Sen_US
dc.contributor.authorDean, Wen_US
dc.contributor.authorHemberger, Men_US
dc.contributor.authorReik, Wen_US
dc.date.accessioned2012-05-29T06:13:46Z-
dc.date.available2012-05-29T06:13:46Z-
dc.date.issued2008en_US
dc.identifier.citationPlos Genetics, 2008, v. 4 n. 6en_US
dc.identifier.issn1553-7390en_US
dc.identifier.urihttp://hdl.handle.net/10722/148567-
dc.description.abstractDNA methylation patterns are reprogrammed in primordial germ cells and in preimplantation embryos by demethylation and subsequent de novo methylation. It has been suggested that epigenetic reprogramming may be necessary for the embryonic genome to return to a pluripotent state. We have carried out a genome-wide promoter analysis of DNA methylation in mouse embryonic stem (ES) cells, embryonic germ (EG) cells, sperm, trophoblast stem (TS) cells, and primary embryonic fibroblasts (pMEFs). Global clustering analysis shows that methylation patterns of ES cells, EG cells, and sperm are surprisingly similar, suggesting that while the sperm is a highly specialized cell type, its promoter epigenome is already largely reprogrammed and resembles a pluripotent state. Comparisons between pluripotent tissues and pMEFs reveal that a number of pluripotency related genes, including Nanog, Lefty1 and Tdgf1, as well as the nucleosome remodeller Smarcd1, are hypomethylated in stem cells and hypermethylated in differentiated cells. Differences in promoter methylation are associated with significant differences in transcription levels in more than 60% of genes analysed. Our comparative approach to promoter methylation thus identifies gene candidates for the regulation of pluripotency and epigenetic reprogramming. While the sperm genome is, overall, similarly methylated to that of ES and EG cells, there are some key exceptions, including Nanog and Lefty1, that are highly methylated in sperm. Nanog promoter methylation is erased by active and passive demethylation after fertilisation before expression commences in the morula. In ES cells the normally active Nanog promoter is silenced when targeted by de novo methylation. Our study suggests that reprogramming of promoter methylation is one of the key determinants of the epigenetic regulation of pluripotency genes. Epigenetic reprogramming in the germline prior to fertilisation and the reprogramming of key pluripotency genes in the early embryo is thus crucial for transmission of pluripotency. © 2008 Farthing et al.en_US
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosgenetics.org/en_US
dc.relation.ispartofPLoS Geneticsen_US
dc.subject.meshAnimalsen_US
dc.subject.meshCells, Cultureden_US
dc.subject.meshChromosomal Proteins, Non-Histone - Genetics - Metabolismen_US
dc.subject.meshDna Methylationen_US
dc.subject.meshEpidermal Growth Factor - Genetics - Metabolismen_US
dc.subject.meshEpigenesis, Geneticen_US
dc.subject.meshFemaleen_US
dc.subject.meshGene Expression Regulation, Developmentalen_US
dc.subject.meshGenomeen_US
dc.subject.meshHomeodomain Proteins - Genetics - Metabolismen_US
dc.subject.meshLeft-Right Determination Factorsen_US
dc.subject.meshMaleen_US
dc.subject.meshMembrane Glycoproteins - Genetics - Metabolismen_US
dc.subject.meshMembrane Proteins - Genetics - Metabolismen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred Strainsen_US
dc.subject.meshMicroarray Analysisen_US
dc.subject.meshNeoplasm Proteins - Genetics - Metabolismen_US
dc.subject.meshNuclear Reprogrammingen_US
dc.subject.meshPluripotent Stem Cells - Physiologyen_US
dc.subject.meshPromoter Regions, Geneticen_US
dc.subject.meshSpermatozoa - Physiologyen_US
dc.subject.meshStem Cells - Physiologyen_US
dc.subject.meshTransforming Growth Factor Beta - Genetics - Metabolismen_US
dc.titleGlobal mapping of DNA methylation in mouse promoters reveals epigenetic reprogramming of pluripotency genesen_US
dc.typeArticleen_US
dc.identifier.emailNg, RK:rayng@pathology.hku.hken_US
dc.identifier.authorityNg, RK=rp00273en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1371/journal.pgen.1000116en_US
dc.identifier.pmid18584034-
dc.identifier.scopuseid_2-s2.0-45349086923en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-45349086923&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume4en_US
dc.identifier.issue6en_US
dc.identifier.eissn1553-7404-
dc.identifier.isiWOS:000260410300011-
dc.publisher.placeUnited Statesen_US
dc.identifier.citeulike2937918-

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