Epigenetic Control of Apolipoprotein E Expression Mediates Gender-Specific Hematopoietic Regulation.
Epigenetic Control of Apolipoprotein E Expression Mediates Gender-Specific Hematopoietic Regulation.
复制标题
载脂蛋白 E 表达的表观遗传控制介导性别特异性造血调节。
DOI：
10.1002/stem.2214
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Godley,LucyA
中科院分区：
文献类型：
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作者：
Vasanthakumar,Aparna;Zullow,Hayley;Lepore,JanetB;Thomas,Kenya;Young,Natalie;Anastasi,John;Reardon,CatherineA;Godley,LucyA
遗传改变在正常和恶性血细胞发育的控制中起着核心作用。我们在这里证明了截断的DNA甲基转移酶3B异构体DNMT3B7的表达，已经被证明可以改变细胞表观遗传模式，减少造血干细胞和祖细胞（HSPCs）的总数，并显着减少女性激素微环境中的血细胞重建。从mmdnmt3b7转基因胚胎中分离的HSPCs基因表达谱鉴定载脂蛋白E（Apoe）过表达。控制apoe表达的CpG岛在转nmt3b7的HSPCs中表达的修饰胞嘧啶水平较低，与观察到的基因表达增加相对应。此外，我们观察到移植了dnmt3b7转基因HSPCs的雌性小鼠的脾脏和骨髓表达非常高水平的apoe。最后，将apoe过表达的HSPCs引入男性受体会减少骨髓移植，这与我们在女性受体中最初的观察结果一致。我们的工作揭示了HSPC内在表观遗传变化与作用于这些细胞的外源内分泌因子之间的动态相互作用，以调节HSPC的植入和重建效率。我们已经确定了一种新的机制，通过这种机制，性别特异性激素调节HSC功能，这可以作为在HSC功能有限的情况下增加造血的靶点。StemCells2015;33:3643 - 3654
AbstractEpigenetic alterations play a central role in the control of normal and malignant blood cell development. We demonstrate here that expression of a truncated DNA methyltransferase 3B isoform DNMT3B7, which has been shown to alter cellular epigenetic patterns, decreases the overall number of hematopoietic stem and progenitor cells (HSPCs), and markedly diminishes blood cell reconstitution within the female hormonal microenvironment. Gene expression profiling of HSPCs isolated fromDNMT3B7transgenic embryos identifiedApolipoprotein E(Apoe) as overexpressed. The CpG island controllingApoeexpression had lower levels of modified cytosines inDNMT3B7transgenic HSPCs, corresponding with the observed increase in gene expression. Furthermore, we observed that spleens and bone marrows of female mice transplanted withDNMT3B7transgenic HSPCs express very high levels ofApoe. Finally, the introduction ofApoe-overexpressing HSPCs into male recipients decreased bone marrow engraftment, recapitulating our original observations in female recipients. Our work reveals a dynamic interplay between the intrinsic epigenetic changes in HSPCs and extrinsic endocrine factors acting on these cells to regulate the efficiency of HSPC engraftment and reconstitution. We have identified a novel mechanism by which gender-specific hormones modulate HSPC function, which could serve as a target for augmenting hematopoiesis in cases with limited HSC functionality. StemCells2015;33:3643–3654