Journal Article

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

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

2013

Overview

Maternal genomic imprinting is crucial for the maintenance of adult stem cells, which is accomplished by maintaining long-term haematopoietic stem cell quiescence. Epigenetic control of adult stem cells A new study by Linheng Li and colleagues investigates the effect of deletion of the H19 differentially methylated region (H19-DMR) in haematopoietic stem cells. The DMR is known to control expression of the imprinted H19 and Igf2 genes from the H19 – Igf2 locus, restricting H19 expression to the maternal allele and Igf2 to the paternal allele. The authors report the predominant expression of a list of maternally expressed growth-restricting imprinted genes in long-term haematopoietic stem cells (LT-HSCs), but not in proliferating short-term HSCs, suggesting a crucial role for genomic imprinting in maintaining quiescent LT-HSCs. The epigenetic regulation of imprinted genes by monoallelic DNA methylation of either maternal or paternal alleles 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 , 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 locus 5 , 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 1 . In addition, H19 serves as a source of miR-675, which restricts Igf1r 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–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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/532/1542 / Adult Stem Cells - cytology / Adult Stem Cells - physiology / Analysis / Animals / Control / Epigenesis, Genetic - genetics / Gene Expression Regulation, Developmental / Genomic Imprinting / Hematopoietic stem cells / Humanities and Social Sciences / Insulin-Like Growth Factor II - genetics / Insulin-Like Growth Factor II - metabolism / Insulin-like growth factors / letter / Methods / Mice / multidisciplinary / Quantitative trait loci / Receptor, IGF Type 1 - genetics / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / Science / Signal Transduction / Transcriptional Activation