Dataset Information

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

ABSTRACT: Cellular senescence is a well-orchestrated programmed process involved in age-related pathologies, tumor suppression and embryonic development. TGF-?/Smad is one of the predominant pathways that regulate damage-induced and developmentally programmed senescence. Here we show that canonical TGF-? signaling promotes senescence via miR-29-induced loss of H4K20me3. Mechanistically, oxidative stress triggers TGF-? signaling. Activated TGF-? 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-?/miR-29 pathway contributes to cardiac aging in vivo. Disruption of TGF-? 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.

SUBMITTER: Lyu G

PROVIDER: S-EPMC6028646 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Lyu Guoliang G Guan Yiting Y Zhang Chao C Zong Le L Sun Lei L Huang Xiaoke X Huang Li L Zhang Lijun L Tian Xiao-Li XL Zhou Zhongjun Z Tao Wei W

Nature communications 20180702 1

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 ...[more]

PMID: 29967491

Similar Datasets

Project description:Cellular Senescence is associated with organismal aging and related pathologies. Previously, we reported that plasminogen activator inhibitor-1 (PAI-1) is an essential mediator of senescence and a potential therapeutic target for preventing aging-related pathologies. In this study, we investigate the efficacies of PAI-1 inhibitors in both in vitro and in vivo models of homocysteine (Hcy)-induced cardiovascular aging. Elevated Hcy, a known risk factor of cardiovascular diseases, induces endothelial senescence as evidenced by increased senescence-associated ?-Gal positivity (SA-?-Gal), flattened cellular morphology, and cylindrical appearance of cellular nuclei. Importantly, inhibition of PAI-1 by small molecule inhibitors reduces the number of SA-?-Gal positive cells, normalizes cellular morphology and nuclear shape. Furthermore, while Hcy induces the levels of senescence regulators PAI-1, p16, p53 and integrin ?3, and suppresses catalase expression, treatment with PAI-1 inhibitors blocks the Hcy-induced stimulation of senescence cadres, and reverses the Hcy-induced suppression of catalase, indicating that PAI-1 specific small molecule inhibitors are efficient to prevent Hcy-induced cellular senescence. Our in vivo study shows that the levels of integrin ?3, a recently identified potential regulator of cellular senescence, and its interaction with PAI-1 are significantly elevated in Hcy-treated heart tissues. In contrast, Hcy suppresses antioxidant gene regulator Nrf2 expression in hearts. However, co-treatment with PAI-1 inhibitor completely blocks the stimulation of Hcy-induced induction of integrin ?3 and reverses Nrf2 expression. Collectively these in vitro and in vivo studies indicate that pharmacological inhibition of PAI-1 improves endothelial and cardiac health by suppressing the pro-senescence effects of hyperhomocysteinemia through suppression of Hcy-induced master regulators of cellular senescence PAI-1 and integrin ?3. Therefore, PAI-1 inhibitors are promising drugs for amelioration of hyperhomocysteinemia-induced vascular aging and aging-related disease.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets