Hematopoiesis under telomere attrition at the single-cell resolution.
Hematopoiesis under telomere attrition at the single-cell resolution.
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单细胞分辨率下端粒磨损下的造血作用。
DOI：
10.1038/s41467-021-27206-7
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发表时间：
2021-11-25
影响因子：
16.6
通讯作者：
Colla S
中科院分区：
文献类型：
--
作者：
Thongon N;Ma F;Santoni A;Marchesini M;Fiorini E;Rose A;Adema V;Ganan-Gomez I;Groarke EM;Gutierrez-Rodrigues F;Chen S;Lockyer P;Schneider S;Bueso-Ramos C;Montalban-Bravo G;Class CA;Soltysiak KA;Pellegrini M;Sahin E;Bertuch AA;DiNardo CD;Garcia-Manero G;Young NS;Dwyer K;Colla S
在端粒缩短的情况下，导致造血干细胞功能下降的分子机制尚不完全清楚。鉴于单细胞技术的最新进展，我们试图重新定义端粒磨损下的小鼠和人类造血干细胞的转录和表观遗传学格局，端粒磨损是由端粒酶复合体基因中的致病种系变异引起的。在这里，我们表明，端粒磨损通过细胞固有的免疫信号反应上调，维持造血干细胞在持续的代谢激活和向巨核细胞谱系分化，这直接损害了造血干细胞的自我更新能力，最终导致它们的耗竭。从机制上讲，我们证明了使用寡脱氧核苷酸A151(包含端粒DNA的TTAGGG基序的四个重复)靶向IFI20x/IFI16胞浆DNA传感器家族的成员，克服了端粒功能障碍的造血干细胞中的干扰素信号激活以及这些细胞向巨核细胞系的倾斜分化。这项研究挑战了历史假说，即端粒磨损通过诱导细胞凋亡、自噬或衰老来限制造血干细胞的增殖潜力，并提示靶向IFI16信号轴可能在影响端粒维持的条件下防止造血干细胞功能下降。在端粒缩短的情况下，导致造血干细胞功能下降的分子机制尚不完全清楚。在这里，作者证明了由影响端粒酶复合体基因的突变诱导的具有短端粒的造血干细胞通过激活IFI16介导的干扰素反应而向巨核细胞分化。
The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells’ self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells’ skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance. The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. Here the authors demonstrate that hematopoietic stem cells with short telomeres induced by mutations affecting telomerase complex genes undergo differentiation towards megakaryopoiesis through the activation of the IFI16-mediated interferon response.
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DOI：
10.1038/nrg3246
发表时间：
2012-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
30.8
作者：
Corces, M. Ryan;Buenrostro, Jason D.;Wu, Beijing;Greenside, Peyton G.;Chan, Steven M.;Koenig, Julie L.;Snyder, Michael P.;Pritchard, Jonathan K.;Kundaje, Anshul;Gkeenleaf, William J.;Majeti, Ravindra;Chang, Howard Y.
通讯作者：
Chang, Howard Y.
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
5.9
作者：
Fok WC;Niero ELO;Dege C;Brenner KA;Sturgeon CM;Batista LFZ
通讯作者：
Batista LFZ
影响因子：
4.5
作者：
Liu, Na;Yin, Yu;Liu, Lin
通讯作者：
Liu, Lin