Thrombopoietin protects hematopoietic stem cells from retrotransposon-mediated damage by promoting an antiviral response.
Thrombopoietin protects hematopoietic stem cells from retrotransposon-mediated damage by promoting an antiviral response.
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DOI：
10.1084/jem.20170997
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发表时间：
2018-05-07
期刊：
影响因子：
--
通讯作者：
Porteu F
中科院分区：
文献类型：
--
作者：
Barbieri D;Elvira-Matelot E;Pelinski Y;Genève L;de Laval B;Yogarajah G;Pecquet C;Constantinescu SN;Porteu F
反转录转座子的繁殖诱导基因组不稳定。它们在造血干细胞中的作用尚不清楚。Barbieri等人的研究表明，逆转录转座子的表达和动员与辐照后HSC的长期损伤有关。这些作用被自我更新的细胞因子THPO通过诱导干扰素样反应来抵消。维持基因组完整性对于保存造血干细胞（HSC）潜能至关重要。逆转录转座子通过RNA中间体在基因组中传播，与自我更新丧失、衰老和DNA损伤有关。然而，它们在造血干细胞中的作用尚未得到解决。在这里，我们发现小鼠造血干细胞表达各种逆转录因子（REs），包括长分散元件-1 （L1）最近的家族成员，在照射后进一步增加。通过小鼠表达工程人类L1逆转录转位报告盒和逆转录抑制剂，我们证明L1转位发生在体内，并参与辐照诱导的持久性γ - h2ax灶和HSC功能丧失。因此，RE代表了一个重要的内在HSC威胁。此外，我们发现血小板生成素（一种关键的HSC维持因子）通过在HSC中促进强有力的干扰素样抗病毒基因反应的能力，抑制了RE活性。这揭示了一种新的机制，使造血干细胞能够最大限度地减少辐照引起的损伤，并加强DNA损伤、REs和抗病毒免疫之间的联系。
Propagation of retrotransposons induces genomic instability. Their roles in HSCs remain poorly studied. Barbieri et al. show that retrotransposon expression and mobilization are involved in long-lasting HSC impairment upon irradiation. These effects are counteracted by the self-renewal cytokine THPO through induction of interferon-like response. Maintenance of genomic integrity is crucial for the preservation of hematopoietic stem cell (HSC) potential. Retrotransposons, spreading in the genome through an RNA intermediate, have been associated with loss of self-renewal, aging, and DNA damage. However, their role in HSCs has not been addressed. Here, we show that mouse HSCs express various retroelements (REs), including long interspersed element-1 (L1) recent family members that further increase upon irradiation. Using mice expressing an engineered human L1 retrotransposition reporter cassette and reverse transcription inhibitors, we demonstrate that L1 retransposition occurs in vivo and is involved in irradiation-induced persistent γH2AX foci and HSC loss of function. Thus, RE represents an important intrinsic HSC threat. Furthermore, we show that RE activity is restrained by thrombopoietin, a critical HSC maintenance factor, through its ability to promote a potent interferon-like, antiviral gene response in HSCs. This uncovers a novel mechanism allowing HSCs to minimize irradiation-induced injury and reinforces the links between DNA damage, REs, and antiviral immunity.
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影响因子：
14.9
作者：
Belancio VP;Roy-Engel AM;Pochampally RR;Deininger P
通讯作者：
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影响因子：
14.9
作者：
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DOI：
10.1073/pnas.1100273108
发表时间：
2011-12-20
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
23.9
作者：
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通讯作者：
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影响因子：
64.5
作者：
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通讯作者：
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