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Maternal imprinting at the H19–Igf2 locus maintains adult haematopoietic stem cell quiescence


The epigenetic regulation of imprinted genes by monoallelic DNA methylation of either maternal or paternal alleles is critical for embryonic growth and development1. Imprinted genes were recently shown to be expressed in mammalian adult stem cells to support self-renewal of neural and lung stem cells2,3,4; 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 locus5, 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 allele1. In addition, H19 serves as a source of miR-675, which restricts Igf1r expression6. 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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Figure 1: Defective LT-HSCs in mH19ΔDMR/+ mice.
Figure 2: Compromised HSC function in mH19ΔDMR/+ mice.
Figure 3: Activation of Igf2–FoxO3 signalling in mH19ΔDMR/+ mice.
Figure 4: Igf1r regulation and rescue by genetic blockage of Igf2–Igf1r signalling.

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Data deposits

The microarray and RNA-seq data have been deposited in ArrayExpress under accession numbers E-MTAB-1644 and E-MTAB-1628, respectively.


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We thank M. Hembree, T. Johnson, H. Marshall, B. Lewis, D. Dukes, C. Semerad, J. Park and A. Box for technical support, and members of the Li laboratory for scientific discussion. We thank J. Lu and Y. Huang for communications about miR-675 and Let-7. We thank K. Tannen for editing. This work was supported by the Stowers Institute for Medical Research and by the Department of Biotechnology, Ministry of Science and Technology, Government of India, as an overseas associateship to A. Venkatraman. M. Bartolomei is supported by the National Institutes of Health (GM51279).

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Authors and Affiliations



A.V. performed experiments, analysed data and wrote the manuscript. X.H. provided training, performed transplantations and RNA-seq. F.T., J.T., M.C., L.P., X.Z., A.P., H.L., J.P. M.Z., J.H. and T.C. performed part of the experiments. M.B. contributed the mouse lines. L.L. directed the overall project and co-wrote the manuscript. All authors contributed to reading and editing the manuscript.

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Correspondence to Linheng Li.

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Venkatraman, A., He, X., Thorvaldsen, J. et al. Maternal imprinting at the H19–Igf2 locus maintains adult haematopoietic stem cell quiescence. Nature 500, 345–349 (2013).

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