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

机译：产妇在H19-Igf2基因座上的印记维持成年造血干细胞的静止

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摘要

Linheng Li及同事完成的一项新的研究工作研rn究的是，造血干细胞中H19“差异化甲基化区rn域“(H19-DMR)的删除所产生的效应。DMRrn已知控制印记基因H79和lgf2从H19-lgf2位点rn的表达，将H19的表达限制于母方等位基因，rn将lgf2的表达限制于父方等位基因。作者报告rn了一系列由母方表达的生长限制印记基因在rn“长期造血干细胞”(LT-HSCs)中、而不是rn在增殖中的短期HSCs中的优势表达，说明基rn因组印记在维持静态LT-HSCs中起一个关键rn作用。%The epigenetic regulation of imprinted genes by monoallelic DNA methylation of either maternal or paternal alkies is critical for embryonic growth and development~1. Imprinted genes were recently shown to be expressed in mammalian adult stem cells to support self-renewal of neural and lung stem cells~(2-4); 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 locus~5, in long-term haematopoietic stem cells and their downregu-lation 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 Igflr expression~6. 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-Igfrl 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 Igt'2 upregulation and increased translation of Igflr, which is normally suppressed by H19-derived miR-675. Similarly, genetic inactivation of Igflr 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.
机译：Linheng Li及同事完成的一项新的研究工作研rn究的是，造血干细胞中H19“差异化甲基化区rn域“(H19-DMR)的删除所产生的效应。DMRrn已知控制印记基因H79和lgf2从H19-lgf2位点rn的表达，将H19的表达限制于母方等位基因，rn将lgf2的表达限制于父方等位基因。作者报告rn了一系列由母方表达的生长限制印记基因在rn“长期造血干细胞”(LT-HSCs)中、而不是rn在增殖中的短期HSCs中的优势表达，说明基rn因组印记在维持静态LT-HSCs中起一个关键rn作用。%The epigenetic regulation of imprinted genes by monoallelic DNA methylation of either maternal or paternal alkies is critical for embryonic growth and development~1. Imprinted genes were recently shown to be expressed in mammalian adult stem cells to support self-renewal of neural and lung stem cells~(2-4); 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 locus~5, in long-term haematopoietic stem cells and their downregu-lation 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 Igflr expression~6. 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-Igfrl 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 Igt'2 upregulation and increased translation of Igflr, which is normally suppressed by H19-derived miR-675. Similarly, genetic inactivation of Igflr 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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  • 来源
    《Nature》 |2013年第7462期|345-349qt3|共6页
  • 作者

    Aparna Venkatraman; Xi C. He; Joanne L. Thorvaldsen; Ryohichi Sugimura; John M. Perry; Fang Tao; Meng Zhao; Matthew K. Christenson; Rebeca Sanchez; Jaclyn Y. Yu; Lai Peng; Jeffrey S. Haug; Ariel Paulson; Hua Li; Xiao-bo Zhong; Thomas L. Clemens; Marisa S. Bartolomei; Linheng Li;

  • 作者单位

    Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA,Centre for Stem Cell Research, Christian Medical College, Vellore 632002, India;

    Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;

    Department of Cell & Developmental Biology,University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;

    Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;

    Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;

    Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;

    Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;

    Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA,Cell Therapy and Genetics Laboratory, Institute de Recerca Vail d'hebron, Barcelona 08035, Spain;

    Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;

    Department of Pharmacology,Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA;

    Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;

    Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;

    Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;

    Department of Pharmacology,Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA;

    Center for Musculoskeletal Research, Johns Hopkins Medicine, Baltimore, Maryland 21287, USA;

    Department of Cell & Developmental Biology,University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA,Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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