The association between Alu hypomethylation and severity of type 2 diabetes mellitus

Thongsroy, Jirapan; Patchsung, Maturada; Mutirangura, Apiwat

doi:10.1186/s13148-017-0395-6

Cited by 37 publications

(45 citation statements)

References 34 publications

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“…This result is similar to a previous study demonstrating the positive correlation between the history of catch up growth and increased Alu methylation [28]. In addition, the correlation between reduced Alu methylation levels and increased quantity of DNA lesions explained why individuals with Alu hypomethylation exhibit an increased risk of disabilities related to aging, such as osteoporosis and diabetes-related hypertension [29,30]. Cells with a normal p53 function can recognize DNA damage and consequently halt cell proliferation [48][49][50][51].…”

Section: Discussionsupporting

confidence: 79%

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Alu siRNA to Increase Alu Element Methylation and Prevent DNA Damage

et al. 2018

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Global DNA hypomethylation promoting genomic instability leads to cancer and deterioration of human health with age. Aim: To invent a biotechnology that can reprogram this process. Methods: We used Alu siRNA to direct Alu interspersed repetitive sequences methylation in human cells. We evaluated the correlation between DNA damage and Alu methylation levels. Results: We observed an inverse correlation between Alu element methylation and endogenous DNA damage in white blood cells. Cells transfected with Alu siRNA exhibited high Alu methylation levels, increased proliferation, reduced endogenous DNA damage and improved resistance to DNA damaging agents. Conclusion: Alu methylation stabilizes the genome by preventing accumulation of DNA damage. Alu siRNA could be useful for evaluating reprograming of the global hypomethylation phenotype in cancer and aging cells. DNA methylation at interspersed repetitive sequences (IRSs) plays an important role in maintaining genome stability. Cells with IRS hypomethylation exhibit increased mutation rates [1,2]. Here, we tested whether DNA damage, an alteration in the chemical structure of DNA and a precursor to mutation [3], plays a role in mediating how global hypomethylation promotes genomic instability. Our recent study found that global hypomethylation is associated with plasma 8-hydroxy-2 -deoxyguanosine (8-OHdG) in biliary atresia patients [4]. Moreover, urinary 8-OHdG, DNA strand breaks and global DNA hypomethylation are associated with low serum folate [5] and oxidative stress [6]. Therefore, we hypothesized that the human genome may use DNA methylation in IRSs to prevent DNA damage.This study developed a technology to add DNA methylation at Alu elements. The human genome contains greater than one million Alu elements [7]. Several reports demonstrated de novo methylation by siRNA in plants [8][9][10]. In human cells, small RNA was used to promote DNA methylation, shRNA for long interspersed element-1 (LINE-1) and hepatitis B virus, and siRNA for HIV-1 promoter region [11][12][13]. There are many types of IRS such as Alu elements, LINE-1, and human endogenous retrovirus [14][15][16][17]. To increase DNA methylation, we tested siRNA to unique sequences and several IRS sequences. Our preliminary trial demonstrated that only Alu siRNA could increase methylation of the target sequences. Here, we evaluated whether Alu siRNA is a useful tool to explore the role of global hypomethylation in genomic instability [18].Alu hypomethylation may play a role in causing genomic instability in cancer and aging cells. Genomic instability, the main enabling characteristic of cancer and aging processes [18,19], may mainly be promoted by IRS hypomethylation. IRS hypomethylation is commonly observed both in aging [14,20] and cancer cells [21]. IRS

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Section: Discussionsupporting

confidence: 79%

“…In younger individuals, Alu methylation is directly correlated with growth rate [28]. Alu hypomethylation is associated with the severity of conditions involved in the deterioration of human health with age, such as osteoporosis [29] and diabetes mellitus [30].…”

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confidence: 99%

Alu siRNA to Increase Alu Element Methylation and Prevent DNA Damage

et al. 2018

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“…Human RIND-EDSBs are localized within hypermethylated regions (7). Genomewide hypomethylation, a common epigenomic change in aging human cells, causes several health problems such as osteoporosis and hypertension in diabetes mellitus patients (2,(43)(44)(45). Genome-wide hypomethylation is also a common epigenomic change in cancer (46,47).…”

Section: Discussionmentioning

confidence: 99%

Reduction in replication‐independent endogenous DNA double‐strand breaks promotes genomic instability during chronological aging in yeast

et al. 2018

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The mechanism that causes genomic instability in nondividing aging cells is unknown. Our previous study of mutant yeast suggested that 2 types of replication-independent endogenous DNA double-strand breaks (RIND-EDSBs) exist and that they play opposing roles. The first type, known as physiologic RIND-EDSBs, were ubiquitous in the G phase of both yeast and human cells in certain genomic locations and may act as epigenetic markers. Low RIND-EDSB levels were found in mutants that lacked chromatin-condensing proteins, such as the high-mobility group box (HMGB) proteins and Sir2. The second type is referred to as pathologic RIND-EDSBs. High pathological RIND-EDSB levels were found in DSB repair mutants. Under normal physiologic conditions, these excess RIND-EDSBs are repaired in much the same way as DNA lesions. Here, chronological aging in yeast reduced physiological RIND-EDSBs and cell viability. A strong correlation was observed between the reduction in RIND-EDSBs and viability in aging yeast cells ( r = 0.94, P < 0.0001). We used galactose-inducible HO endonuclease (HO) and nhp6a∆, an HMGB protein mutant, to evaluate the consequences of reduced physiological RIND-EDSB levels. The HO-induced cells exhibited a sustained reduction in RIND-EDSBs at various levels for several days. Interestingly, we found that lower physiologic RIND-EDSB levels resulted in decreased cell viability ( r = 0.69, P < 0.0001). Treatment with caffeine, a DSB repair inhibitor, increased pathological RIND-EDSBs, which were distinguished from physiologic RIND-EDSBs by their lack of sequences prior to DSB in untreated cells [odds ratio (OR) ≤1]. Caffeine treatment in both the HO-induced and nhp6a∆ cells markedly increased OR ≤1 breaks. Therefore, physiological RIND-EDSBs play an epigenetic role in preventing pathological RIND-EDSBs, a type of DNA damage. In summary, the reduction of physiological RIND-EDSB level is a genomic instability mechanism in chronologically aging cells.-Thongsroy, J., Patchsung, M., Pongpanich, M., Settayanon, S., Mutirangura, A. Reduction in replication-independent endogenous DNA double-strand breaks promotes genomic instability during chronological aging in yeast.

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“…Previous studies reported an age-dependent decline in genomic DNA methylation, both in global DNA and in Alu elements [13,14,17]. DNA Alu hypomethylation may promote an enhanced retrotransposon activity and genomic instability [12] and is associated with the severity of some age-related diseases [14][15][16][17].…”

Section: Discussionmentioning

confidence: 99%

“…Alu hypomethylation has been found during aging [13] and it has been associated with the severity of age-related diseases such as diabetes [14], cancer [15], osteoporosis [16] and cardiovascular diseases [17]. Interestingly, hypomethylation and epigenetic age are delayed in centenarians' offspring [18,19], which are considered an optimal model to study biomarkers associated with human longevity.…”

Section: Introductionmentioning

confidence: 99%

Nutritional Factors Modulating Alu Methylation in an Italian Sample from The Mark-Age Study Including Offspring of Healthy Nonagenarians

et al. 2019

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Alu hypomethylation promotes genomic instability and is associated with aging and age-related diseases. Dietary factors affect global DNA methylation, leading to changes in genomic stability and gene expression with an impact on longevity and the risk of disease. This preliminary study aims to investigate the relationship between nutritional factors, such as circulating trace elements, lipids and antioxidants, and Alu methylation in elderly subjects and offspring of healthy nonagenarians. Alu DNA methylation was analyzed in sixty RASIG (randomly recruited age-stratified 2 of 15 individuals from the general population) and thirty-two GO (GeHA offspring) enrolled in Italy in the framework of the MARK-AGE project. Factor analysis revealed a different clustering between Alu CpG1 and the other CpG sites. RASIG over 65 years showed lower Alu CpG1 methylation than those of GO subjects in the same age class. Moreover, Alu CpG1 methylation was associated with fruit and whole-grain bread consumption, LDL2-Cholesterol and plasma copper. The preserved Alu methylation status in GO, suggests Alu epigenetic changes as a potential marker of aging. Our preliminary investigation shows that Alu methylation may be affected by food rich in fibers and antioxidants, or circulating LDL subfractions and plasma copper.

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The association between Alu hypomethylation and severity of type 2 diabetes mellitus

Cited by 37 publications

References 34 publications

Alu siRNA to Increase Alu Element Methylation and Prevent DNA Damage

Alu siRNA to Increase Alu Element Methylation and Prevent DNA Damage

Reduction in replication‐independent endogenous DNA double‐strand breaks promotes genomic instability during chronological aging in yeast

Nutritional Factors Modulating Alu Methylation in an Italian Sample from The Mark-Age Study Including Offspring of Healthy Nonagenarians

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