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TGF-β signaling alters H4K20me3 status via miR-29 and contributes to cellular senescence and cardiac aging
- Source :
- Nature Communications, Vol 9, Iss 1, Pp 1-13 (2018), Nature Communications
- Publication Year :
- 2018
- Publisher :
- Nature Portfolio, 2018.
-
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.<br />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.
- Subjects :
- 0301 basic medicine
Senescence
Male
Aging
Science
Primary Cell Culture
General Physics and Astronomy
SMAD
Biology
medicine.disease_cause
Heterocyclic Compounds, 4 or More Rings
General Biochemistry, Genetics and Molecular Biology
Article
Epigenesis, Genetic
Histones
03 medical and health sciences
Mice
Transforming Growth Factor beta
medicine
Human Umbilical Vein Endothelial Cells
Myocyte
Animals
Humans
Myocytes, Cardiac
Epigenetics
lcsh:Science
Cellular Senescence
Multidisciplinary
HEK 293 cells
Heart
General Chemistry
Histone-Lysine N-Methyltransferase
DNA Methylation
Fibroblasts
Embryo, Mammalian
Cell biology
Mice, Inbred C57BL
MicroRNAs
Oxidative Stress
030104 developmental biology
HEK293 Cells
Cell culture
lcsh:Q
Female
Oxidative stress
Transforming growth factor
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 9
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....78fbca88fc5b3bf48f90359119674e00