Linheng Li及同事完成的一項(xiàng)新的研究工作研究的是，造血干細(xì)胞中H19“差異化甲基化區(qū)域” (H19-DMR) 的刪除所產(chǎn)生的效應(yīng),。DMR已知控制印記基因H19 和 Igf2從H19–Igf2 位點(diǎn)的表達(dá),，將H19 的表達(dá)限制于母方等位基因，將Igf2的表達(dá)限制于父方等位基因,。作者報(bào)告了一系列由母方表達(dá)的生長(zhǎng)限制印記基因在“長(zhǎng)期造血干細(xì)胞”(LT-HSCs)中,、而不是在增殖中的短期HSCs中的優(yōu)勢(shì)表達(dá)，說(shuō)明基因組印記在維持靜態(tài)LT-HSCs中起一個(gè)關(guān)鍵作用,。
生物谷推薦英文摘要：
Nature doi:10.1038/nature12303
Maternal imprinting at the H19–Igf2 locus maintains adult haematopoietic stem cell quiescence
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
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.
