Age-Associated Decrease of the Histone Methyltransferase SUV39H1 in HSC Perturbs Heterochromatin and B Lymphoid Differentiation.
Age-Associated Decrease of the Histone Methyltransferase SUV39H1 in HSC Perturbs Heterochromatin and B Lymphoid Differentiation.
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DOI：
10.1016/j.stemcr.2016.05.007
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发表时间：
2016-06-14
影响因子：
5.9
通讯作者：
Goodhardt M
中科院分区：
文献类型：
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作者：
Djeghloul D;Kuranda K;Kuzniak I;Barbieri D;Naguibneva I;Choisy C;Bories JC;Dosquet C;Pla M;Vanneaux V;Socié G;Porteu F;Garrick D;Goodhardt M
造血干细胞（HSC）产生B淋巴细胞的能力随着年龄的增长而下降，导致老年人免疫功能受损。在这里，我们发现组蛋白甲基转移酶SUV39H1在人B淋巴细胞分化中发挥重要作用，并且SUV39H1的表达在人和小鼠HSC中随着年龄的增长而下降，导致H3K9三甲基化的整体减少和异染色质功能的紊乱。此外，我们证明SUV39H1是microRNA miR-125b的靶标，miR-125b是一种已知的HSC功能调节剂，miR-125b在人HSC中的表达随着年龄的增长而增加。在年轻HSC中，miR-125b的过表达和SUV39H1的抑制诱导了B细胞电位的丧失。相反，抑制miR-125和强制表达SUV39H1都能提高老年人HSC生成B细胞的能力。我们的发现强调了异染色质调控在HSC衰老和B淋巴生成中的重要性。人HSC中抑制SUV39H1组蛋白甲基转移酶导致HSC中B淋巴细胞生成减少，SUV39H1和全局组蛋白H3K9三甲基化随年龄减少。microRNA miR-125b在HSC中靶向SUV39H1并随年龄增加。抑制miR-125b或过表达SUV39H1可改善老年HSC的B细胞输出。衰老与造血干细胞（HSC）生成B淋巴细胞的能力下降有关。Goodhardt及其同事证明，HSC中与年龄相关的microRNA miR-125b的增加靶向组蛋白甲基转移酶SUV39H1，导致异染色质紊乱和B细胞电位下降。这项研究提出了改善老年人免疫功能的新目标。
The capacity of hematopoietic stem cells (HSC) to generate B lymphocytes declines with age, contributing to impaired immune function in the elderly. Here we show that the histone methyltransferase SUV39H1 plays an important role in human B lymphoid differentiation and that expression of SUV39H1 decreases with age in both human and mouse HSC, leading to a global reduction in H3K9 trimethylation and perturbed heterochromatin function. Further, we demonstrate that SUV39H1 is a target of microRNA miR-125b, a known regulator of HSC function, and that expression of miR-125b increases with age in human HSC. Overexpression of miR-125b and inhibition of SUV39H1 in young HSC induced loss of B cell potential. Conversely, both inhibition of miR-125 and enforced expression of SUV39H1 improved the capacity of HSC from elderly individuals to generate B cells. Our findings highlight the importance of heterochromatin regulation in HSC aging and B lymphopoiesis. Inhibition of SUV39H1 histone methyltransferase in human HSC leads to decreased B lymphopoiesis SUV39H1 and global histone H3K9 trimethylation decrease with age in HSC The microRNA miR-125b targets SUV39H1 in HSC and increases with age Inhibition of miR-125b or overexpression of SUV39H1 improves B cell output of old HSC Aging is associated with a decline in the capacity of hematopoietic stem cells (HSC) to generate B lymphocytes. Goodhardt and colleaguesdemonstrate that an age-associated increase of the microRNA miR-125b in HSC targets the histone methyltransferase SUV39H1, leading to perturbed heterochromatin and a decline of B cell potential. This study suggests new targets to improve immune function in the elderly.