TGF-β signaling alters H4K20me3 status via miR-29 and contributes to cellular senescence and cardiac aging

Guoliang Lyu, Yiting Guan, Chao Zhang, Le Zong, Lei Sun, Xiaoke Huang, Li Huang, Lijun Zhang, Xiao-Li Tian, Zhongjun Zhou and Wei Tao ()
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Guoliang Lyu: Peking University
Yiting Guan: Peking University
Chao Zhang: Peking University
Le Zong: Peking University
Lei Sun: Peking University
Xiaoke Huang: Peking University
Li Huang: Peking University
Lijun Zhang: Peking University
Xiao-Li Tian: Nanchang University
Zhongjun Zhou: The University of Hong Kong
Wei Tao: Peking University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-04994-z

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