title: Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence.
abstract: 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.
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Venkatraman
authors.forename: Xi C
authors.initials: XC
authors.lastname: He
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Thorvaldsen
authors.forename: Ryohichi
authors.initials: R
authors.lastname: Sugimura
authors.forename: John M
authors.initials: JM
authors.lastname: Perry
authors.forename: Fang
authors.initials: F
authors.lastname: Tao
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Christenson
authors.forename: Rebeca
authors.initials: R
authors.lastname: Sanchez
authors.forename: Jaclyn Y
authors.initials: JY
authors.lastname: Yu
authors.forename: Lai
authors.initials: L
authors.lastname: Peng
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Haug
authors.forename: Ariel
authors.initials: A
authors.lastname: Paulson
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Xiao-bo
authors.initials: XB
authors.lastname: Zhong
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Clemens
authors.forename: Marisa S
authors.initials: MS
authors.lastname: Bartolomei
authors.forename: Linheng
authors.initials: L
authors.lastname: Li
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology* / Q000502:physiology*; D000818:Animals; D044127:Epigenesis, Genetic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: C094335:H19 long non-coding RNA; C513121:IGF2 protein, mouse; D062085:RNA, Long Noncoding; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1