Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration.
Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration.
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DOI：
10.1038/s41556-021-00707-9
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发表时间：
2021-07
影响因子：
21.3
通讯作者：
Trompouki E
中科院分区：
文献类型：
--
作者：
Clapes T;Polyzou A;Prater P;Sagar;Morales-Hernández A;Ferrarini MG;Kehrer N;Lefkopoulos S;Bergo V;Hummel B;Obier N;Maticzka D;Bridgeman A;Herman JS;Ilik I;Klaeylé L;Rehwinkel J;McKinney-Freeman S;Backofen R;Akhtar A;Cabezas-Wallscheid N;Sawarkar R;Rebollo R;Grün D;Trompouki E
造血干细胞（HSC）通常处于静止状态，但已进化出应对压力的机制。在这里，我们评估化疗诱导的造血再生。我们在早期恢复期间检测到强大的染色质重组，随后转座元件（TE）的转录增加。 TE 转录物结合并激活先天免疫受体黑色素瘤分化相关蛋白 5 (MDA5)，该蛋白产生炎症反应，这是 HSC 退出静止状态所必需的。缺乏 MDA5 的 HSC 在化疗后表现出受损的炎症反应并保持静止状态，从而具有更好的长期再增殖能力。我们发现，ERV 和 LINE 超家族 TE 拷贝在野生型 HSC 中的过度表达（但在 Mda5−/− HSC 中则不然）导致了它们的循环。相比之下，在敲除 LINE1 家族拷贝后，HSC 保持静止状态。我们的结果表明，TE 转录本作为配体在造血再生过程中激活 MDA5，从而使 HSC 能够产生退出静止状态所需的炎症反应。克拉普斯等人。研究表明，化疗会导致染色质重组和转座元件表达增加，从而促进 MDA5 驱动的炎症反应，从而增强造血再生。
Haematopoietic stem cells (HSCs) are normally quiescent, but have evolved mechanisms to respond to stress. Here, we evaluate haematopoietic regeneration induced by chemotherapy. We detect robust chromatin reorganization followed by increased transcription of transposable elements (TEs) during early recovery. TE transcripts bind to and activate the innate immune receptor melanoma differentiation-associated protein 5 (MDA5) that generates an inflammatory response that is necessary for HSCs to exit quiescence. HSCs that lack MDA5 exhibit an impaired inflammatory response after chemotherapy and retain their quiescence, with consequent better long-term repopulation capacity. We show that the overexpression of ERV and LINE superfamily TE copies in wild-type HSCs, but not in Mda5−/− HSCs, results in their cycling. By contrast, after knockdown of LINE1 family copies, HSCs retain their quiescence. Our results show that TE transcripts act as ligands that activate MDA5 during haematopoietic regeneration, thereby enabling HSCs to mount an inflammatory response necessary for their exit from quiescence. Clapes et al. show that chemotherapy leads to chromatin reorganization and increased expression of transposable elements, which promote an MDA5-driven inflammatory response that enhances haematopoietic regeneration.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.8
作者：
Aktas, Tugce;Ilik, Ibrahim Avsar;Akhtar, Asifa
通讯作者：
Akhtar, Asifa
DOI：
10.3109/10409238.2011.630974
发表时间：
2012-03
影响因子：
6.5
作者：
Bruns AM;Horvath CM
通讯作者：
Horvath CM
DOI：
10.1126/science.aad5497
发表时间：
2016-03-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chuong EB;Elde NC;Feschotte C
通讯作者：
Feschotte C
影响因子：
64.8
作者：
Chelmicki, Tomasz;Roger, Emeline;Bourc'his, Deborah
通讯作者：
Bourc'his, Deborah