TGF-β signaling alters H4K20me3 status via miR-29 and contributes to cellular senescence and cardiac aging.
TGF-β signaling alters H4K20me3 status via miR-29 and contributes to cellular senescence and cardiac aging.
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TGF-β 信号通过 miR-29 改变 H4K20me3 状态，并导致细胞衰老和心脏老化。
DOI：
10.1038/s41467-018-04994-z
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发表时间：
2018-07-02
影响因子：
16.6
通讯作者：
Tao W
中科院分区：
文献类型：
--
作者：
Lyu G;Guan Y;Zhang C;Zong L;Sun L;Huang X;Huang L;Zhang L;Tian XL;Zhou Z;Tao W
细胞衰老是一个精心策划的程序化过程，涉及年龄相关的病理学，肿瘤抑制和胚胎发育。TGF-β/Smad是调节损伤诱导和发育程序性衰老的主要途径之一。在这里，我们表明典型的TGF-β信号通过miR-29诱导的H4 K20 me 3损失促进衰老。在机制上，氧化应激触发TGF-β信号传导。活化的TGF-β信号传导引起miR-29 a和miR-29 c的急性积累，这两者都直接抑制其新靶点Suv 4 - 20 h，从而以Smad依赖性方式降低H4 K20 me 3丰度，这损害了DNA损伤修复和基因组维持。衰老TGF-β/miR-29通路介导的H4 K20 me 3的缺失导致体内心脏衰老破坏TGF-β信号传导恢复H4 K20 me 3并改善老年小鼠的心脏功能。我们的研究强调了衰老调节的顺序机制，从衰老诱导触发到响应信号的激活，然后是特定的表观遗传改变，揭示了心脏衰老的潜在治疗干预。细胞衰老与表观遗传重塑有关。在这里，作者报告说，TGF-β信号转导促进miR-29介导的H4 K20 me 3丢失，从而加速衰老。
Cellular senescence is a well-orchestrated programmed process involved in age-related pathologies, tumor suppression and embryonic development. TGF-β/Smad is one of the predominant pathways that regulate damage-induced and developmentally programmed senescence. Here we show that canonical TGF-β signaling promotes senescence via miR-29-induced loss of H4K20me3. Mechanistically, oxidative stress triggers TGF-β signaling. Activated TGF-β signaling gives rise to acute accumulation of miR-29a and miR-29c, both of which directly suppress their novel target, Suv4-20h, thus reducing H4K20me3 abundance in a Smad-dependent manner, which compromises DNA damage repair and genome maintenance. Loss of H4K20me3 mediated by the senescent TGF-β/miR-29 pathway contributes to cardiac aging in vivo. Disruption of TGF-β signaling restores H4K20me3 and improves cardiac function in aged mice. Our study highlights the sequential mechanisms underlying the regulation of senescence, from senescence-inducing triggers to activation of responsive signaling followed by specific epigenetic alterations, shedding light on potential therapeutic interventions in cardiac aging. Cellular senescence is associated with epigenetic remodeling. Here, the authors report that TGF-β signaling promotes miR-29 mediated loss of H4K20me3 thus accelerating senescence.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.6
作者：
Heid J;Cencioni C;Ripa R;Baumgart M;Atlante S;Milano G;Scopece A;Kuenne C;Guenther S;Azzimato V;Farsetti A;Rossi G;Braun T;Pompilio G;Martelli F;Zeiher AM;Cellerino A;Gaetano C;Spallotta F
通讯作者：
Spallotta F
影响因子：
64.5
作者：
Burd CE;Sorrentino JA;Clark KS;Darr DB;Krishnamurthy J;Deal AM;Bardeesy N;Castrillon DH;Beach DH;Sharpless NE
通讯作者：
Sharpless NE
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
全基因组甲基化谱揭示了人类衰老速度的定量观点。
影响因子：
16
作者：
Hannum, Gregory;Guinney, Justin;Zhao, Ling;Zhang, Li;Hughes, Guy;Sadda, SriniVas;Klotzle, Brandy;Bibikova, Marina;Fan, Jian-Bing;Gao, Yuan;Deconde, Rob;Chen, Menzies;Rajapakse, Indika;Friend, Stephen;Ideker, Trey;Zhang, Kang
通讯作者：
Zhang, Kang