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

摘要

The epigenetic regulation of imprinted genes via 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 up-regulation of growth-restricting imprinted genes, including within the H19-Igf2 locus, in long-term hematopoietic stem cells (LT-HSCs) and their down-regulation upon HSC activation and proliferation. A differentially methylated region (DMR) 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 also serves as a source of miR-675, which restricts Igf1r expression. We demonstrated that conditional deletion of the maternal but not the paternal H19-DMR reduced adult HSC quiescence, a state required for long-term maintenance of HSCs, and compromised HSC function. Maternal-specific H19-DMR deletion resulted in activation of the Igf2-Igfr1 pathway as revealed 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 HSCs. Mechanistically, maternal-specific H19-DMR deletion led to Igf2 up-regulation and increased translation of Igf1r, which is normally suppressed by H19-derived miR-675. Similarly, genetic inactivation of Igf1r partially rescued the H19-DMR deletion phenotype. Our work establishes a novel role for this unique form of epigenetic control at the H19-Igf2 locus in maintaining adult stem cells.