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Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence
Open accessAbstract
The 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.
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“Quiescence is key to maintaining this stem cell population, and the loss of H19-mediated repression of Igf2 leads to hematopoietic stem cell exhaustion (Venkatraman et al., 2013).”
From The Aging Epigenome (2016) · cites this paper as Venkatraman et al., 2013
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“Furthermore, H19-mediated repression of Igf2 has been demonstrated to be important for the maintenance of hematopoietic stem cell quiescence (Venkatraman et al., 2013).”
From The Aging Epigenome (2016) · cites this paper as Venkatraman et al., 2013
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Self-citationParental imprinting of the mouse insulin-like growth factor II gene
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Research works printed but not linked: 2
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- Haug, J. S. et al. N-cadherin expression level distinguishes reserved versus primed states of hematopoietic stem cells. Cell Stem Cell 2, 367–379 (2008) · DOI
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Metadata
- Authors
- Venkatraman, A., He, X. C., Thorvaldsen, J. L., Sugimura, R., Perry, J. M., Tao, F., Zhao, M., Christenson, M. K., Sanchez, R., Yu, J. Y., Peng, L., Haug, J. S., Paulson, A., Li, H., Zhong, X.-B., Clemens, T. L., Bartolomei, M. S., & Li, L.
- Affiliations
- Stowers Institute for Medical Research (US)
- University of Pennsylvania (US)
- University of Kansas Medical Center (US)
- Johns Hopkins University (US)
- Corresponding author
- Li, Linheng
- ORCID
- Venue
- Nature
- Published
- 2013-07-17
- Volume
- 500
- Issue
- 7462
- Pages
- 345-349
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3896866
- OpenAlex
- W2081038378
- Cited by
- 296
- References
- 44
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 21 · 2023: 19 · 2022: 21 · 2021: 15 · 2020: 21 · 2019: 31 · 2018: 25 · 2017: 39 · 2016: 27 · 2015: 34 · 2014: 22 · 2013: 5
- FWCI
- 19.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM087376, GM-51279, R01GM051279, R37GM051279)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- genomic imprinting, hematopoietic stem cells, stem cell quiescence, H19 differentially methylated region, H19, insulin-like growth factor II, miR-675, IGF-1 receptor, FOXO3, DNA methylation
- MeSH terms
- Animals, Insulin-Like Growth Factor II, Signal Transduction, Transcriptional Activation, Receptor, IGF Type 1, Genomic Imprinting, Gene Expression Regulation, Developmental, Epigenesis, Genetic, Mice, Adult Stem Cells, RNA, Long Noncoding
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