Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence.
Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence.
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DOI：
10.1038/nature12303
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发表时间：
2013-08-15
期刊：
影响因子：
64.8
通讯作者：
Li, Linheng
中科院分区：
文献类型：
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作者：
Venkatraman, Aparna;He, Xi C.;Thorvaldsen, Joanne L.;Sugimura, Ryohichi;Perry, John M.;Tao, Fang;Zhao, Meng;Christenson, Matthew K.;Sanchez, Rebeca;Yu, Jaclyn Y.;Peng, Lai;Haug, Jeffrey S.;Paulson, Ariel;Li, Hua;Zhong, Xiao-bo;Clemens, Thomas L.;Bartolomei, Marisa S.;Li, Linheng
印迹基因的表观遗传调控通过母亲或父亲等位基因的单等位基因DNA甲基化是胚胎生长和发育的关键。印记基因最近被证明在哺乳动物成体干细胞中表达，以支持神经和肺干细胞的自我更新;然而，印记本身在成体干细胞中的作用仍然难以捉摸。在这里，我们显示了在长期造血干细胞（LT-HSC）中生长限制性印记基因（包括H19-Igf 2基因座内）的上调及其在HSC活化和增殖后的下调。H19上游的差异甲基化区域（DMR）（H19-DMR）作为印迹控制区域，决定了来自母本等位基因的H19和来自父本等位基因的Igf 2的相互表达。此外，H19也是限制Igf 1 r表达的miR-675的来源。我们证明，条件性删除母亲而不是父亲的H19-DMR减少成年HSC静止，长期维持HSC所需的状态，并损害HSC功能。母体特异性H19-DMR缺失导致Igf 2-Igfr 1通路的激活，如磷酸化Foxo 3（一种失活形式）从细胞核易位至细胞质和Foxo 3介导的细胞周期停滞的释放所揭示的，从而导致HSC的激活、增殖和最终耗尽增加。从机制上讲，母体特异性H19-DMR缺失导致Igf 2上调和Igf 1 r翻译增加，这通常被H19衍生的miR-675抑制。类似地，Igf 1 r的遗传失活部分挽救了H19-DMR缺失表型。我们的工作为H19-Igf 2基因座的这种独特的表观遗传控制形式在维持成体干细胞中建立了一种新的作用。
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.
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影响因子：
64.5
作者：
Sugimura R;He XC;Venkatraman A;Arai F;Box A;Semerad C;Haug JS;Peng L;Zhong XB;Suda T;Li L
通讯作者：
Li L
DOI：
10.1073/pnas.0810221106
发表时间：
2009-02-17
影响因子：
11.1
作者：
Klinakis, Apostolos;Szabolcs, Matthias;Efstratiadis, Argiris
通讯作者：
Efstratiadis, Argiris
影响因子：
23.9
作者：
Haug, Jeffrey S.;He, Xi C.;Li, Linheng
通讯作者：
Li, Linheng
影响因子：
8.5
作者：
Kang, H. M.;Park, S.;Kim, H.
通讯作者：
Kim, H.
影响因子：
21.3
作者：
通讯作者：
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