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.
Highlights
Cellular senescence is a well-orchestrated programmed process involved in age-related pathologies, tumor suppression and embryonic development
The results showed that H4K20me1, -me[2], and -me[3] exhibited prominent down-regulation in senescent mouse embryonic fibroblasts (MEFs) (Fig. 1a; Supplementary Fig. 1a–c)
After the mice were fed with E-616452 to inhibit TGF-β signaling, decreased H4K20me[3] abundance was observed in the livers of 1-year-old mice, but a substantial increase was observed in the livers of 2-year-old mice (Supplementary Fig. 7c). These results suggest that modulation of H4K20me[3] by TGF-β signaling might be involved in cardiac aging, probably because the cardiovascular system consumes a relatively large amount of oxygen and it is likely to be more susceptible than other tissues to hyperoxic stress
Summary
Cellular senescence is a well-orchestrated programmed process involved in age-related pathologies, tumor suppression and embryonic development. 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. In vivo and in vitro models have confirmed that TGF-β signaling, activated by SASP or other developmental cues, regulates senescence via up-regulation of p15 and/or p21 in damage-induced and developmental senescence[18] These findings indicate that TGF-β pathway plays an important role in senescence as one of the key sensors mediating senescent signaling in response to environmental stresses and endogenous signals. We demonstrate a sequential regulatory axis, in which H4K20me[3], as a responsive downstream epigenetic effector of the TGF-β/Smad pathway, is negatively regulated by miR-29 to regulate cellular senescence. Our study reveals an epigenetics-based responsive pathway that drives alterations in histone modification status during cellular senescence
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
