The DOI matches its Crossref record; 43 of the 44 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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
In the citing paper
“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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849
Trapnell, C., Williams, B. A., Pertea, G., Mortazavi, A., Kwan, G., van Baren, M. J., Salzberg, S. L., Wold, B. J., & Pachter, L. (2010) · Nature Biotechnology · doi:10.1038/nbt.1621 · Cited by 15,556
Smyth, G. K. (2004) · Statistical Applications in Genetics and Molecular Biology · doi:10.2202/1544-6115.1027 · Cited by 11,829
TopHat: discovering splice junctions with RNA-Seq
Trapnell, C., Pachter, L. S., & Salzberg, S. L. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp120 · Cited by 11,682
Exploration, normalization, and summaries of high density oligonucleotide array probe level data
Irizarry, R. A. (2003) · Biostatistics · doi:10.1093/biostatistics/4.2.249 · Cited by 10,603
Bolstad, B. M., Irizarry, R. A., Åstrand, M., & Speed, T. P. (2003) · Bioinformatics · doi:10.1093/bioinformatics/19.2.185 · Cited by 8,328
Summaries of Affymetrix GeneChip probe level data
Irizarry, R. A. (2003) · Nucleic Acids Research · doi:10.1093/nar/gng015 · Cited by 4,837
Identification of the haematopoietic stem cell niche and control of the niche size
Zhang, J., Niu, C. S., Ye, L., Huang, H., He, X. C., Tong, W.-G., Ross, J., Haug, J., Johnson, T. J., Feng, J. Q., et al. (2003) · Nature · doi:10.1038/nature02041 · Cited by 2,948
Self-citationParental imprinting of the mouse insulin-like growth factor II gene
DeChiara, T. M., Robertson, E. J., & Efstratiadis, A. (1991) · Cell · doi:10.1016/0092-8674(91)90513-x · Cited by 1,804
FoxOs Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress
Tothova, Z., Kollipara, R., Huntly, B. J., Lee, B. H., Castrillon, D. H., Cullen, D. E., McDowell, E. P., Lazo-Kallanian, S., Williams, I. R., Sears, C., et al. (2007) · Cell · doi:10.1016/j.cell.2007.01.003 · Cited by 1,562
The let-7 MicroRNA Represses Cell Proliferation Pathways in Human Cells
Johnson, C. D., Esquela-Kerscher, A., Stefani, G., Byrom, M., Kelnar, K., Ovcharenko, D., Wilson, M., Wang, X., Shelton, J., Shingara, J., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1083 · Cited by 1,224
Zhao, Z., Tavoosidana, G., Sjölinder, M., Göndör, A., Mariano, P., Wang, S., Kanduri, C., Lezcano, M., Sandhu, K. S., Singh, U., et al. (2006) · Nature Genetics · doi:10.1038/ng1891 · Cited by 957
PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention
Zhang, J., Grindley, J. C., Yin, T., Jayasinghe, S., He, X. C., Ross, J. T., Haug, J. S., Rupp, D., Porter-Westpfahl, K. S., Wiedemann, L. M., et al. (2006) · Nature · doi:10.1038/nature04747 · Cited by 817
Self-citationThe H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r
Keniry, A., Oxley, D., Monnier, P., Kyba, M., Dandolo, L., Smits, G., & Reik, W. (2012) · Nature Cell Biology · doi:10.1038/ncb2521 · Cited by 806
Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells
Stadtfeld, M., Apostolou, E., Akutsu, H., Fukuda, A., Follett, P., Natesan, S., Kono, T., Shioda, T., & Hochedlinger, K. (2010) · Nature · doi:10.1038/nature09017 · Cited by 801
Zac1 Regulates an Imprinted Gene Network Critically Involved in the Control of Embryonic Growth
Varrault, A., Gueydan, C., Delalbre, A., Bellmann, A., Houssami, S., Aknin, C., Séverac, D., Chotard, L., Kahli, M., Digarcher, A. L., et al. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.09.003 · Cited by 478
Yang, L., Bryder, D., Adolfsson, J., Nygren, J., Månsson, R., Sigvardsson, M., & Jacobsen, S. E. W. (2004) · Blood · doi:10.1182/blood-2004-06-2159 · Cited by 469
Rb Regulates Interactions between Hematopoietic Stem Cells and Their Bone Marrow Microenvironment
Walkley, C. R., Shea, J. M., Sims, N. A., Purton, L. E., & Orkin, S. H. (2007) · Cell · doi:10.1016/j.cell.2007.03.055 · Cited by 424
Akashi, K., He, X., Chen, J., Iwasaki, H., Niu, C. S., Steenhard, B. M., Zhang, J., Haug, J., & Li, L. (2002) · Blood · doi:10.1182/blood-2002-06-1780 · Cited by 368
Self-citationNoncanonical Wnt Signaling Maintains Hematopoietic Stem Cells in the Niche
Sugimura, R., He, X., Venkatraman, A., Arai, F., Box, A., Semerad, C. L., Haug, J. S., Peng, L., Zhong, X.-B., Suda, T., et al. (2012) · Cell · doi:10.1016/j.cell.2012.05.041 · Cited by 306
Self-citationPostnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis
Ferrón, S. R., Charalambous, M., Radford, E. J., McEwen, K. R., Wildner, H., Hind, E., Morante‐Redolat, J. M., Laborda, J., Guillemot, F., Bauer, S. R., et al. (2011) · Nature · doi:10.1038/nature10229 · Cited by 294
Zou, P., Yoshihara, H., Hosokawa, K., Tai, I., Shinmyozu, K., Tsukahara, F., Maru, Y., Nakayama, K., Nakayama, K. I., & Suda, T. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.07.003 · Cited by 289
Miller, C., & Eaves, C. J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.25.13648 · Cited by 261
Genomic imprinting: employing and avoiding epigenetic processesPreprint
Bartolomei, M. S. (2009) · Genes & Development · doi:10.1101/gad.1841409 · Cited by 251
Self-citationThe Importance of Imprinting in the Human Placenta
Frost, J. M., & Moore, G. E. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001015 · Cited by 247
5-Fluorouracil spares hemopoietic stem cells responsible for long-term repopulation.
Lerner, C. P., & Harrison, D. E. (1990) · PubMed · Cited by 246
Regulation of growth and metabolism by imprinted genes
Smith, F. M., Garfield, A. S., & Ward, A. (2006) · Cytogenetic and Genome Research · doi:10.1159/000090843 · Cited by 196
Perry, J. M., He, X., Sugimura, R., Grindley, J. C., Haug, J. S., Ding, S., & Li, L. (2011) · Genes & Development · doi:10.1101/gad.17421911 · Cited by 191
Self-citationAdult mouse hematopoietic stem cells: purification and single-cell assays
Ema, H., Morita, Y., Yamazaki, S., Matsubara, A., Seita, J., Tadokoro, Y., Kondo, H., Takano, H., & Nakauchi, H. (2006) · Nature Protocols · doi:10.1038/nprot.2006.447 · Cited by 184
The let-7-Imp axis regulates ageing of the Drosophila testis stem-cell niche
Toledano, H., D’Alterio, C., Czech, B., Levine, E., & Jones, D. L. (2012) · Nature · doi:10.1038/nature11061 · Cited by 169
N-Cadherin Expression Level Distinguishes Reserved versus Primed States of Hematopoietic Stem Cells
Haug, J. S., He, X., Grindley, J. C., Wunderlich, J. P., Gaudenz, K., Ross, J. T., Paulson, A., Wagner, K. P., Xie, Y., Zhu, R., et al. (2008) · Cell stem cell · doi:10.1016/j.stem.2008.01.017 · Cited by 156
Self-citationLung Stem Cell Self-Renewal Relies on BMI1-Dependent Control of Expression at Imprinted Loci
Zacharek, S. J., Brainson, C. F., Lau, A. N., Gludish, D. W., Chou, A. Y., Ho, J. W. K., Zamponi, R., Gazit, R., Bock, C., Jäger, N., et al. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.07.007 · Cited by 133
Conditional mutagenesis in mice with heat shock promoter-driven cre transgenes
Dietrich, P., Dragatsis, I., Xuan, S., Zeitlin, S. O., & Efstratiadis, A. (2000) · Mammalian Genome · doi:10.1007/s003350010037 · Cited by 131
Smad4 is critical for self-renewal of hematopoietic stem cells
Karlsson, G., Blank, U., Moody, J. L., Ehinger, M., Singbrant, S., Deng, C., & Karlsson, S. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20060465 · Cited by 129
Yu, W., Imoto, I., Inoue, J., Onda, M., Emi, M., & Inazawa, J. (2006) · Oncogene · doi:10.1038/sj.onc.1209899 · Cited by 103
Igf1r as a therapeutic target in a mouse model of basal-like breast cancer
Klinakis, A., Szabolcs, M. J., Chen, G., Xuan, S., Hibshoosh, H. H., & Efstratiadis, A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810221106 · Cited by 99
Imprinted Genes That Regulate Early Mammalian Growth Are Coexpressed in Somatic Stem Cells
Berg, J. S., Lin, K. K., Sonnet, C., Boles, N. C., Weksberg, D. C., Nguyen, H., Holt, L. J., Rickwood, D., Daly, R. J., & Goodell, M. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026410 · Cited by 84
Niedernberg, A., Tunaru, S., Blaukat, A., Ardati, A., & Kostenis, E. (2003) · Cellular Signalling · doi:10.1016/s0898-6568(02)00119-5 · Cited by 72
Genomic imprinting mechanisms in embryonic and extraembryonic mouse tissues
Hudson, Q. J., Kuliński, T. M., Huetter, S. P., & Barlow, D. P. (2010) · Heredity · doi:10.1038/hdy.2010.23 · Cited by 69
Thorvaldsen, J. L., Fedoriw, A., Nguyen, S. C., & Bartolomei, M. S. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.4.1245-1258.2006 · Cited by 55
Self-citationNecdin restricts proliferation of hematopoietic stem cells during hematopoietic regeneration
Kubota, Y., Osawa, M., Jakt, L. M., Yoshikawa, K., & Nishikawa, S. (2009) · Blood · doi:10.1182/blood-2009-07-230292 · Cited by 51
Smad signal transduction : Smads in proliferation, differentiation and disease
ten Dijke, P., & Heldin, C. (2006) · Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) · doi:10.1007/1-4020-4709-6 · Cited by 19
Kang, H. M., Park, S. H., & Kim, H. (2011) · Cell Proliferation · doi:10.1111/j.1365-2184.2011.00755.x · Cited by 7
Flagged first, then by citations
1 of the 44 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- Thorvaldsen, J. L., Fedoriw, A. M., Nguyen, S. & Bartolomei, M. S. Developmental profile of H19 differentially methylated domain (DMD) deletion alleles reveals multiple roles of the DMD in regulating allelic expression and DNA methylation at the imprinted H19/Igf2 locus. Mol. Cell. Biol. 26, 1245–1258 (2006) · DOI
- 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
Cited by
Sorted by citations
Epigenetic modulators, modifiers and mediators in cancer aetiology and progression
Feinberg, A. P., Koldobskiy, M. A., & Göndör, A. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.13 · Cited by 841
Gene regulation in the immune system by long noncoding RNAs
Chen, Y. G., Satpathy, A. T., & Chang, H. Y. (2017) · Nature Immunology · doi:10.1038/ni.3771 · Cited by 694
Ren, J., Ding, L., Zhang, D., Shi, G., Xu, Q., Shen, S., Wang, Y., Wang, T., & Hou, Y. (2018) · Theranostics · doi:10.7150/thno.25541 · Cited by 698
Cabezas‐Wallscheid, N., Klimmeck, D., Hansson, J., Lipka, D. B., Reyes, A., Wang, Q., Weichenhan, D., Lier, A., von Paleske, L., Renders, S., et al. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.07.005 · Cited by 590
Raveh, E., Matouk, I., Gilon, M., & Hochberg, A. (2015) · Molecular Cancer · doi:10.1186/s12943-015-0458-2 · Cited by 503
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
