Cytoplasmic DNA: sources, sensing, and role in aging and disease

Miller, Karl; Victorelli, Stella; Salmonowicz, Hanna; Dasgupta, Nirmalya; Liu, Tianhui; Passos, João F.; Adams, Peter D.

doi:10.1016/j.cell.2021.09.034

Cited by 131 publications

(118 citation statements)

References 222 publications

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“…Our study used human iPSC-derived microglia (iPS-Mg) from iPSC lines from people with distinct genetic backgrounds to construct an in vitro model of ELS. We report here that excessive GC at the stage of primitive haematopoiesis during microglial differentiation, resulted in increased interferon-alpha signalling, frequent formation of cGAS (a positive marker for micronuclei 18 , Miller et al 2021), positive micronuclei indicating possible genomic instability, and senescence-like features in differentiated iPS-Mg.…”

Section: Introductionmentioning

confidence: 64%

Glucocorticoid receptor activation during human microglial differentiation leads to genomic instability and senescence

Wei

Arber

Wray

et al. 2022

Preprint

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Early life stress, prenatal exposure to glucocorticoids (GCs), confers a higher risk of psychiatric and neurodevelopmental disorders in children. Increasingly, the importance of microglia in these disorders has been recognised. Studies on GCs exposure during microglial development have been limited, and there are few, if any, human studies. We established an in vitro model of ELS by continuous pre-expoure of human iPS-microglia to GCs during primitive haematopoiesis (the critical stage of iPS-microglial differentiation) and then examined how this exposure affected the microglial phenotype as they differentiated and matured to microglia. The iPS-microglia predominately expressed glucocorticoid receptors over mineralocorticoid receptors, and the GR-α splice variant. Chronic GCs exposure during primitive haematopoiesis was able to recapitulate in vivo ELS effects. Thus pre-exposure to prolonged GCs resulted in increased type I interferon signalling, the presence of Cyclic GMP-AMP synthase-positive (cGAS) micronuclei, and cellular senescence in the matured iPS-microglia. The findings from this in vitro ELS model have ramifications for the responses of microglia in the pathogenesis of GC-mediated ELS-associated disorders such as schizophrenia, attention-deficit hyperactivity disorder and autistic spectrum disorder.

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Section: Introductionmentioning

confidence: 64%

Glucocorticoid receptor activation during human microglial differentiation leads to genomic instability and senescence

Wei

Arber

Wray

et al. 2022

Preprint

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“…As described in a recent review [23], there are many different types of cytoplasmic dsDNA of nuclear origin, and most of them are positive for histone markers. Due to the limitation of the combination of antibodies used for triple staining, we used histone H2B as a histone marker.…”

Section: Discussionmentioning

confidence: 93%

“…After 3 days of TFAM protein knockdown, a lot of double-stranded DNA dots were detected in the cytoplasm of the HeLa cells. Histones are positive markers for nuclear-origin DNA in the cytoplasm, and negative markers for mitochondrial DNA and mitochondrial-origin DNA in the cytoplasm [23]. These dots did not co-localize with histones, suggesting that they were not nuclear-derived DNA.…”

Section: Decreased Tfam or Gba Induces An Increase In Ectopic Mitocho...mentioning

confidence: 94%

Evaluation of Ectopic Mitochondrial DNA in HeLa Cells

Hussan

Matsui

2022

CIMB

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The presence of ectopic DNA in the cytoplasm induces inflammation and cell death. It has been widely reported that leakage of nuclear DNA into the cytoplasm can mainly be sensed by cyclic GMP-AMP synthase (cGAS). We recently reported that mitochondria-derived cytoplasmic double-stranded DNA (dsDNA) that has escaped lysosomal degradation induces significant cytotoxicity in cultured cells and in vivo. Cytoplasmic mitochondrial DNA is assumed to be involved in various diseases and disorders, and more and more papers have been published confirming this. On the other hand, the current method for evaluating mitochondrial DNA in the cytoplasm may not be quantitative. Here, we introduce in detail a method to evaluate ectopic mitochondrial DNA in cells. This method is useful in basic research as well as in the study of aging, Parkinson’s disease, Alzheimer’s disease, heart failure, autoimmune diseases, cancer, and other conditions.

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“…The top 10 KEGG pathways (those enriched in the shortest paths) are shown in Table 6 ( Turi et al, 2019 ; Jia et al, 2021 ; Chothani et al, 2019 ; Yin et al, 2021 ; Manhas and Rath, 2020 ; Li et al, 2018 ; Nakajima et al, 2019 ; Hosseini et al, 2021 ; Critchley et al, 2018 ; Lathe et al, 2014 ; Margiotta, 2021 ; Nickel et al, 2002 ; Chen et al, 2020 ; Luo et al, 2020 ; Miller et al, 2021 ; Stadtman et al, 2005 ; Bonifácio et al, 2021 ; Blachier et al, 2020 ; Kumar et al, 2017 ; Récher, 2021 ; Klemm and Ruland, 2006 ). The most frequently enriched KEGG pathway was “ribosome” (enriched in eight shortest paths; Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

The Inflamm-Aging Model Identifies Key Risk Factors in Atherosclerosis

Chen

Yao

et al. 2022

Front. Genet.

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Background: Atherosclerosis, one of the main threats to human life and health, is driven by abnormal inflammation (i.e., chronic inflammation or oxidative stress) during accelerated aging. Many studies have shown that inflamm-aging exerts a significant impact on the occurrence of atherosclerosis, particularly by inducing an immune homeostasis imbalance. However, the potential mechanism by which inflamm-aging induces atherosclerosis needs to be studied more thoroughly, and there is currently a lack of powerful prediction models.Methods: First, an improved inflamm-aging prediction model was constructed by integrating aging, inflammation, and disease markers with the help of machine learning methods; then, inflamm-aging scores were calculated. In addition, the causal relationship between aging and disease was identified using Mendelian randomization. A series of risk factors were also identified by causal analysis, sensitivity analysis, and network analysis.Results: Our results revealed an accelerated inflamm-aging pattern in atherosclerosis and suggested a causal relationship between inflamm-aging and atherosclerosis. Mechanisms involving inflammation, nutritional balance, vascular homeostasis, and oxidative stress were found to be driving factors of atherosclerosis in the context of inflamm-aging.Conclusion: In summary, we developed a model integrating crucial risk factors in inflamm-aging and atherosclerosis. Our computation pipeline could be used to explore potential mechanisms of related diseases.

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Cytoplasmic DNA: sources, sensing, and role in aging and disease

Cited by 131 publications

References 222 publications

Glucocorticoid receptor activation during human microglial differentiation leads to genomic instability and senescence

Glucocorticoid receptor activation during human microglial differentiation leads to genomic instability and senescence

Evaluation of Ectopic Mitochondrial DNA in HeLa Cells

The Inflamm-Aging Model Identifies Key Risk Factors in Atherosclerosis

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