Autolysosomal degradation of cytosolic chromatin fragments antagonizes oxidative stress–induced senescence

Han, Xiaobin; Chen, Honghan; Gong, Hui; Tang, Xiaoqiang; Huang, Ning; Xu, Weitong; Tai, Haoran; Zhang, Gongchang; Zhao, Tingting; Gong, Chuhui; Wang, Shuang; Yu, Yang; Xiao, Hengyi

doi:10.1074/jbc.ra119.010734

Cited by 50 publications

(36 citation statements)

References 38 publications

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“…Additionally, we observed elevated superoxide levels in MSC from obese subjects. Inflammation and lipid peroxidation in obesity may increase oxidative stress, which in turn has been shown to induce senescence through p53-specific signaling (Han et al, 2020). However, additional studies need to be done conducted to further evaluate this potential mechanism.…”

Section: Discussionmentioning

confidence: 99%

Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells

Conley

Hickson

Kellogg

et al. 2020

Front. Cell Dev. Biol.

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Background: Chronic inflammatory conditions like obesity may adversely impact the biological functions underlying the regenerative potential of mesenchymal stromal/stem cells (MSC). Obesity can impair MSC function by inducing cellular senescence, a growth-arrest program that transitions cells to a pro-inflammatory state. However, the effect of obesity on adipose tissue-derived MSC in human subjects remains unclear. We tested the hypothesis that obesity induces senescence and dysfunction in human MSC. Methods: MSC were harvested from abdominal subcutaneous fat collected from obese and age-matched non-obese subjects (n = 40) during bariatric or kidney donation surgeries, respectively. MSC were characterized, their migration and proliferation assessed, and cellular senescence evaluated by gene expression of cell-cycle arrest and senescence-associated secretory phenotype markers. In vitro studies tested MSC effect on injured human umbilical vein endothelial cells (HUVEC) function. Results: Mean age was 59 ± 8 years, 66% were females. Obese subjects had higher body-mass index (BMI) than non-obese. MSC from obese subjects exhibited lower proliferative capacities than non-obese-MSC, suggesting decreased function, whereas their migration remained unchanged. Senescent cell burden and phenotype, manifested as p16, p53, IL-6, and MCP-1 gene expression, were significantly upregulated in obese subjects' MSC. BMI correlated directly with expression of p16, p21, and IL-6. Furthermore, co-incubation with non-obese, but not with obese-MSC, restored VEGF expression and tube formation that were blunted in injured HUVEC. Conclusion: Human obesity triggers an early senescence program in adipose tissue-derived MSC. Thus, obesity-induced cellular injury may alter efficacy of this endogenous repair system and hamper the feasibility of autologous transplantation in obese individuals.

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Section: Discussionmentioning

confidence: 99%

Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells

Conley

Hickson

Kellogg

et al. 2020

Front. Cell Dev. Biol.

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“…This is mainly mediated by the downregulation of DNase 2α, the unique endonuclease in the lysosomes, resulting in a decreased DNA degradation capacity of autolysosomes. Consistently, restoration of autolysosomal function with metformin or rapamycin treatment reduces CCF accumulation in oxidative stress-induced senescence ( Han et al, 2020 ). Another work also reported that in HRasV12-induced senescent HDF, two cytoplasmic DNase enzymes DNase2 and TREX1 can remove CCF before they accumulate.…”

Section: Formation Of Ccfmentioning

confidence: 81%

Cytoplasmic chromatin fragments—from mechanisms to therapeutic potential

Miller

Dasgupta

Liu

et al. 2021

eLife

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Senescent cells, damaged cells that permanently exit the cell cycle, play important roles in development, tissue homeostasis, and tumorigenesis. Although many of these roles are beneficial in acute responses to stress and damage, the persistent accumulation of senescent cells is associated with many chronic diseases through their proinflammatory senescence-associated secretory phenotype (SASP). SASP expression is linked to DNA damage; however, the mechanisms that control the SASP are incompletely understood. More recently, it has been shown that senescent cells shed fragments of nuclear chromatin into the cytoplasm, so called cytoplasmic chromatin fragments (CCF). Here, we provide an overview of the current evidence linking DNA damage to the SASP through the formation of CCF. We describe mechanisms of CCF generation and their functional role in senescent cells, with emphasis on therapeutic potential.

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“…The protein samples were treated with protease inhibitors to reduce degeneration. 40 ug of total protein was subjected to western blot with the protocol described previously [ 25 ]. The following antibodies were used: anti-PHF19 antibody (Cell Signaling Technology), anti-SIRT2 antibody (Proteintech), anti-GAPDH (Protein tech).…”

Section: Methodsmentioning

confidence: 99%

PHD Finger Protein 19 Promotes Cardiac Hypertrophy via Epigenetically Regulating SIRT2

Cheng

Wang

et al. 2021

Cardiovasc Toxicol

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Epigenetic regulations essentially participate in the development of cardiomyocyte hypertrophy. PHD finger protein 19 (PHF19) is a polycomb protein that controls H3K36me3 and H3K27me3. However, the roles of PHF19 in cardiac hypertrophy remain unknown. Here in this work, we observed that PHF19 promoted cardiac hypertrophy via epigenetically targeting SIRT2. In angiotensin II (Ang II)-induced cardiomyocyte hypertrophy, adenovirus-mediated knockdown of Phf19 reduced the increase in cardiomyocyte size, repressed the expression of hypertrophic marker genes Anp and Bnp, as well as inhibited protein synthesis. By contrast, Phf19 overexpression promoted Ang II-induced cardiomyocyte hypertrophy in vitro. We also knocked down Phf19 expression in mouse hearts in vivo. The results demonstrated that Phf19 knockdown reduced Ang II-induced decline in cardiac fraction shortening and ejection fraction. Phf19 knockdown also inhibited Ang II-mediated increase in heart weight, reduced cardiomyocyte size, and repressed the expression of hypertrophic marker genes in mouse hearts. Further mechanism studies showed that PHF19 suppressed the expression of SIRT2, which contributed to the function of PHF19 during cardiomyocyte hypertrophy. PHF19 bound the promoter of SIRT2 and regulated the balance between H3K27me3 and H3K36me3 to repress the expression of SIRT2 in vitro and in vivo. In human hypertrophic hearts, the overexpression of PHF19 and downregulation of SIRT2 were observed. Of importance, PHF19 expression was positively correlated with hypertrophic marker genes ANP and BNP but negatively correlated with SIRT2 in human hypertrophic hearts. Therefore, our findings demonstrated that PHF19 promoted the development of cardiac hypertrophy via epigenetically regulating SIRT2.

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Autolysosomal degradation of cytosolic chromatin fragments antagonizes oxidative stress–induced senescence

Cited by 50 publications

References 38 publications

Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells

Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells

Cytoplasmic chromatin fragments—from mechanisms to therapeutic potential

PHD Finger Protein 19 Promotes Cardiac Hypertrophy via Epigenetically Regulating SIRT2

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