Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity.
Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity.
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DOI：
10.3389/fphys.2021.726345
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发表时间：
2021
影响因子：
4
通讯作者：
Zhao JW
中科院分区：
文献类型：
--
作者：
Wang DX;Zhu XD;Ma XR;Wang LB;Dong ZJ;Lin RR;Cao YN;Zhao JW
端粒长度的维持对于延缓细胞的复制性衰老至关重要。生长分化因子11 （growth differentiation factor 11, GDF11）是否能逆转细胞衰老尚存争议，本研究旨在明确GDF11与端粒维持之间的因果关系。利用CRISPR/Cas9技术和细胞衰老的长期体外培养模型，我们在这里发现GDF11的体外遗传缺失导致端粒长度缩短，端粒逆转录酶（TERT）和端粒RNA组分（TERC）下调，端粒RNA组分是端粒延长的关键酶和RNA组分，端粒酶活性降低。相比之下，重组GDF11和过表达GDF11都能将GDF11KO细胞中TERT的转录恢复到野生型水平。此外，gdf11诱导的端粒缩短缺失可能是由于SMAD2的核进入增强，从而抑制TERT和TERC的转录。我们的研究结果提供了第一个因果证据，证明内源性GDF11在增殖细胞维持端粒长度中起因果作用，为增殖细胞、组织和器官的潜在再生铺平了道路。
Maintenance of telomere length is essential to delay replicative cellular senescence. It is controversial on whether growth differentiation factor 11 (GDF11) can reverse cellular senescence, and this work aims to establish the causality between GDF11 and the telomere maintenance unequivocally. Using CRISPR/Cas9 technique and a long-term in vitro culture model of cellular senescence, we show here that in vitro genetic deletion of GDF11 causes shortening of telomere length, downregulation of telomeric reverse transcriptase (TERT) and telomeric RNA component (TERC), the key enzyme and the RNA component for extension of the telomere, and reduction of telomerase activity. In contrast, both recombinant and overexpressed GDF11 restore the transcription of TERT in GDF11KO cells to the wild-type level. Furthermore, loss of GDF11-induced telomere shortening is likely caused by enhancing the nuclear entry of SMAD2 which inhibits the transcription of TERT and TERC. Our results provide the first proof-of-cause-and-effect evidence that endogenous GDF11 plays a causal role for proliferative cells to maintain telomere length, paving the way for potential rejuvenation of the proliferative cells, tissues, and organs.
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