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Article: Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence

TitleMaternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence
Authors
Issue Date2013
Citation
Nature, 2013, v. 500, n. 7462, p. 345-349 How to Cite?
AbstractThe epigenetic regulation of imprinted genes by monoallelic DNA methylation of either maternal or paternal alleles is critical for embryonic growth and development. Imprinted genes were recently shown to be expressed in mammalian adult stem cells to support self-renewal of neural and lung stem cells; however, a role for imprinting per se in adult stem cells remains elusive. Here we show upregulation of growth-restricting imprinted genes, including in the H19-Igf2 locus, in long-term haematopoietic stem cells and their downregulation upon haematopoietic stem cell activation and proliferation. A differentially methylated region upstream of H19 (H19-DMR), serving as the imprinting control region, determines the reciprocal expression of H19 from the maternal allele and Igf2 from the paternal allele. In addition, H19 serves as a source of miR-675, which restricts Igf1r expression. We demonstrate that conditional deletion of the maternal but not the paternal H19-DMR reduces adult haematopoietic stem cell quiescence, a state required for long-term maintenance of haematopoietic stem cells, and compromises haematopoietic stem cell function. Maternal-specific H19-DMR deletion results in activation of the Igf2-Igfr1 pathway, as shown by the translocation of phosphorylated FoxO3 (an inactive form) from nucleus to cytoplasm and the release of FoxO3-mediated cell cycle arrest, thus leading to increased activation, proliferation and eventual exhaustion of haematopoietic stem cells. Mechanistically, maternal-specific H19-DMR deletion leads to Igf2 upregulation and increased translation of Igf1r, which is normally suppressed by H19-derived miR-675. Similarly, genetic inactivation of Igf1r partly rescues the H19-DMR deletion phenotype. Our work establishes a new role for this unique form of epigenetic control at the H19-Igf2 locus in maintaining adult stem cells. © 2013 Macmillan Publishers Limited. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/295395
ISSN
2023 Impact Factor: 50.5
2023 SCImago Journal Rankings: 18.509
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorVenkatraman, Aparna-
dc.contributor.authorHe, Xi C.-
dc.contributor.authorThorvaldsen, Joanne L.-
dc.contributor.authorSugimura, Ryohichi-
dc.contributor.authorPerry, John M.-
dc.contributor.authorTao, Fang-
dc.contributor.authorZhao, Meng-
dc.contributor.authorChristenson, Matthew K.-
dc.contributor.authorSanchez, Rebeca-
dc.contributor.authorYu, Jaclyn Y.-
dc.contributor.authorPeng, Lai-
dc.contributor.authorHaug, Jeffrey S.-
dc.contributor.authorPaulson, Ariel-
dc.contributor.authorLi, Hua-
dc.contributor.authorZhong, Xiao Bo-
dc.contributor.authorClemens, Thomas L.-
dc.contributor.authorBartolomei, Marisa S.-
dc.contributor.authorLi, Linheng-
dc.date.accessioned2021-01-18T15:46:46Z-
dc.date.available2021-01-18T15:46:46Z-
dc.date.issued2013-
dc.identifier.citationNature, 2013, v. 500, n. 7462, p. 345-349-
dc.identifier.issn0028-0836-
dc.identifier.urihttp://hdl.handle.net/10722/295395-
dc.description.abstractThe epigenetic regulation of imprinted genes by monoallelic DNA methylation of either maternal or paternal alleles is critical for embryonic growth and development. Imprinted genes were recently shown to be expressed in mammalian adult stem cells to support self-renewal of neural and lung stem cells; however, a role for imprinting per se in adult stem cells remains elusive. Here we show upregulation of growth-restricting imprinted genes, including in the H19-Igf2 locus, in long-term haematopoietic stem cells and their downregulation upon haematopoietic stem cell activation and proliferation. A differentially methylated region upstream of H19 (H19-DMR), serving as the imprinting control region, determines the reciprocal expression of H19 from the maternal allele and Igf2 from the paternal allele. In addition, H19 serves as a source of miR-675, which restricts Igf1r expression. We demonstrate that conditional deletion of the maternal but not the paternal H19-DMR reduces adult haematopoietic stem cell quiescence, a state required for long-term maintenance of haematopoietic stem cells, and compromises haematopoietic stem cell function. Maternal-specific H19-DMR deletion results in activation of the Igf2-Igfr1 pathway, as shown by the translocation of phosphorylated FoxO3 (an inactive form) from nucleus to cytoplasm and the release of FoxO3-mediated cell cycle arrest, thus leading to increased activation, proliferation and eventual exhaustion of haematopoietic stem cells. Mechanistically, maternal-specific H19-DMR deletion leads to Igf2 upregulation and increased translation of Igf1r, which is normally suppressed by H19-derived miR-675. Similarly, genetic inactivation of Igf1r partly rescues the H19-DMR deletion phenotype. Our work establishes a new role for this unique form of epigenetic control at the H19-Igf2 locus in maintaining adult stem cells. © 2013 Macmillan Publishers Limited. All rights reserved.-
dc.languageeng-
dc.relation.ispartofNature-
dc.titleMaternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1038/nature12303-
dc.identifier.pmid23863936-
dc.identifier.pmcidPMC3896866-
dc.identifier.scopuseid_2-s2.0-84881668166-
dc.identifier.volume500-
dc.identifier.issue7462-
dc.identifier.spage345-
dc.identifier.epage349-
dc.identifier.eissn1476-4687-
dc.identifier.isiWOS:000323112400035-
dc.identifier.issnl0028-0836-

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