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@#Abstract：Long interspersed element⁃1（LINE⁃1）is the only known active and autonomously transposable retroelement in human cells，which is related to autoimmune diseases and plays important roles in activating and regulating the antiviral innate immunity of cells，especially the level of interferon（IFN）. This paper reviews the mechanisms of several non ⁃ structural proteins from human immunodeficiency virus（HIV），hepatitis B virus（HBV）and other viruses participating in the regulation of LINE ⁃ 1 activity. These mechanisms not only ensure the normal expression of viral genome，but also participate in the cellular innate immunity regulation，the inhibition of which may provide new strategies to develop treatments of diseases caused by viruses.
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@#[摘 要] 长散布元件-1（long interspersed nuclear element-1，LINE-1）逆转录转座子是肿瘤中染色体不稳定、基因组不稳定和遗传异质性的主要标志，并已成为许多疾病发生、发展和不良预后的标志物之一。LINE-1也参与调控免疫系统，并通过多种方式影响免疫微环境。LINE-1逆转录转座子的异常表达可对先天免疫应答产生强烈刺激，激活免疫系统，引发自身免疫和炎症反应。因此，抑制LINE-1的活性已成为多种肿瘤的潜在治疗策略。本文主要综述了LINE-1的调控机制、LINE-1与肿瘤和免疫的相关性以及LINE-1的多种抑制剂，为LINE-1的研究提供了新的认识。
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SIRT7, a sirtuin family member implicated in aging and disease, is a regulator of metabolism and stress responses. It remains elusive how human somatic stem cell populations might be impacted by SIRT7. Here, we found that SIRT7 expression declines during human mesenchymal stem cell (hMSC) aging and that SIRT7 deficiency accelerates senescence. Mechanistically, SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins, thus maintaining the repressive state of heterochromatin at nuclear periphery. Accordingly, deficiency of SIRT7 results in loss of heterochromatin, de-repression of the LINE1 retrotransposon (LINE1), and activation of innate immune signaling via the cGAS-STING pathway. These aging-associated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor. Together, these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.
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SIRT7, a sirtuin family member implicated in aging and disease, is a regulator of metabolism and stress responses. It remains elusive how human somatic stem cell populations might be impacted by SIRT7. Here, we found that SIRT7 expression declines during human mesenchymal stem cell (hMSC) aging and that SIRT7 deficiency accelerates senescence. Mechanistically, SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins, thus maintaining the repressive state of heterochromatin at nuclear periphery. Accordingly, deficiency of SIRT7 results in loss of heterochromatin, de-repression of the LINE1 retrotransposon (LINE1), and activation of innate immune signaling via the cGAS-STING pathway. These aging-associated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor. Together, these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.
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Fundamentos: O nível de metilação global do ADN de leucócitos no sangue tem sido associado ao risco de doença arterial coronariana (DAC), com resultados inconsistentes em diferentes populações. Faltam dados semelhantes da população chinesa, onde diferentes fatores genéticos, de estilo de vida e ambientais podem afetar a metilação do ADN e sua relação com o risco de DCC. Objetivos: Analisar se a metilação global está associada ao risco de doença coronariana na população chinesa. Métodos: Foram incluídos um total de 334 casos de DCC e 788 controles saudáveis. A metilação global do ADN de leucócitos de sangue foi estimada por meio da análise das repetições do LINE-1 usando pirosequenciamento de bissulfito. Resultados: Em uma análise inicial restrita aos controles o nível do LINE-1 diminui significativamente com a idade avançada, colesterol total elevado, e diagnóstico de diabetes. Na análise de caso-controle, a redução da metilação do LINE-1 foi associada ao aumento do risco de DCC, tendo a análise por quartil revelado uma odds ratio (IC 95%) de 0,9 (0,6-1,4), 1,9 (1,3-2,9) e 2,3 (1,6 3.5) para o terceiro, segundo e primeiro (o mais baixo) quartil (P da tendência < 0,001), respectivamente, em comparação com o quarto (o mais alto) quartil. A metilação inferior (< mediana) do LINE-1 esteve associada a 2,2 vezes (IC 95% = 1,7-3,0) o aumento de risco de doença coronariana. As estimativas de risco de DCC menores relacionadas com o LINE-1 tenderam a ser mais fortes entre os indivíduos com maior tercil de homocisteína (P interação = 0,042) e naqueles com diagnóstico de hipertensão arterial (P interação = 0,012). Conclusão: A hipometilação do LINE-1 está ...
Background: Global methylation level in blood leukocyte DNA has been associated with the risk of coronary heart disease (CHD), with inconsistent results in various populations. Similar data are lacking in Chinese population where different genetic, lifestyle and environmental factors may affect DNA methylation and its risk relationship with CHD. Objectives: To examine whether global methylation is associated with the risk of CHD in Chinese population. Methods: A total of 334 cases with CHD and 788 healthy controls were included. Global methylation in blood leukocyte DNA was estimated by analyzing LINE-1 repeats using bisulfite pyrosequencing. Results: In an initial analysis restricted to control subjects, LINE-1 level reduced significantly with aging, elevated total cholesterol, and diagnosis of diabetes. In the case-control analysis, reduced LINE-1 methylation was associated with increased risk of CHD; analysis by quartile revealed odds ratios (95%CI) of 0.9 (0.6-1.4), 1.9 (1.3-2.9) and 2.3 (1.6-3.5) for the third, second and first (lowest) quartile (Ptrend < 0.001), respectively, compared to the fourth (highest) quartile. Lower (<median) LINE-1 methylation was associated with a 2.2-fold (95%CI = 1.7-3.0) increased risk of CHD. The lower LINE-1-related CHD risk estimates tended to be stronger among subjects with the highest tertile of homocysteine (Pinteraction = 0.042) and those with diagnosis of hypertension (Pinteraction = 0.012). Conclusion: LINE-1 hypomethylation is associated with the risk of CHD in Chinese population. Potential CHD risk factors such as older age, elevated total cholesterol, and diagnosis of diabetes may have impact on global DNA methylation, whereby exerting their effect on CHD risk. .
Subject(s)
Aged , Humans , Middle Aged , Asian People/genetics , Coronary Disease/genetics , DNA Methylation/genetics , Long Interspersed Nucleotide Elements/genetics , Age Factors , Body Mass Index , Case-Control Studies , Chi-Square Distribution , China , Coronary Disease/ethnology , Diabetes Complications , Hypertension/complications , Leukocytes , Polymerase Chain Reaction , Reference Values , Risk Assessment , Risk Factors , Sex FactorsABSTRACT
Objective To investigate the effect of retrotransposon LINE-1 encoding proteins LINE-1 ORF-1p on proliferation ability of hepatocellular carcinoma cell lines and hepatic immortalized cell lines. Methods siRNA expression vector for LINE-1 ORF-1 encoding sequence (LINE-1 ORF-1p psilence2.1-U6-siRNA) was structured. Hepatocellular carcinoma cell lines (Bel-7402, SMMC-7721, HepG2) and hepatic immortalized cell line (LO2) were transfected. The effect of LINE-1 ORF-1p siRNA expression vector on the expression of LINE-1 ORF-1 encoding protein LINE-1 ORF-1p was detected using the Western blotting assay. The effect of LINE-1 ORF-1p expression reduction on the proliferation ability of these cells was identified using the MTT method. Result In the hepatocellular carcinoma cells (Bel-7402, SMMC-7721, HepG2) and hepatic immortalized cell (LO2), the transfection of LINE-1 ORF-1p siRNA expression vector reduced the expression level of LINE-1 ORF-1p. Moreover, it significantly inhibited the proliferation of the above cells on the third day (P<0.05). The inhibition rates were as follows: Bel-7402, 51%; HepG2, 63%; SMMC-7721, 40%; and LO2, 43%. Conclusion The inhibition of LINE-1 ORF1p protein expression can inhibit the proliferation ability of hepatocellular carcinoma cells and hepatic immortalized cells.
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BACKGROUND/AIMS: Gastric epithelial dysplasia is considered a precancerous lesion with a variable clinical course. There is disagreement, however, regarding histology-based diagnoses, which has led to confusion in choosing a therapeutic plan. New objective markers are needed to determine which lesions progress to true malignancy. We measured LINE-1 methylation levels, which have been reported to strongly correlate with the global methylation level in gastric epithelial dysplasia and intramucosal cancer. METHODS: A total of 145 tissue samples were analyzed by two histopathologists. All tissues were excised by therapeutic endoscopic mucosal resection and paired with adjacent normal tissue samples. A modified long interspersed nucleotide elements-combined bisulfite restriction analysis (COBRA-LINE-1) method was used. RESULTS: Gastric epithelial dysplasia and intramucosal cancer tissues had significantly lower levels of LINE-1 methylation than adjacent normal gastric tissues. High-grade dysplasia and intramucosal cancer were distinguishable from low-grade dysplasia based on LINE-1 methylation levels. Furthermore, the distinction could be determined with high sensitivity and specificity, as shown by the receiver operating characteristic (ROC) curve (AUC, 0.82; 95% confidence interval, 0.74 to 0.88). CONCLUSIONS: LINE-1 methylation levels may provide a diagnostic tool for identifying high-grade dysplasia and intramucosal cancer.
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Methylation , ROC Curve , Sensitivity and Specificity , SulfitesABSTRACT
Background: Cancer cells are frequently characterized by hypomethylation of the genome including repetitive sequences. This epigenetic process is believed to be associated with several biological causes and consequences in cancer. Therefore, LINE-1 repetitive sequences demethylation in cancer should result in different clinical outcomes. Objective: Recently, we have developed an improved quantitative combined bisulfite restriction analysis PCR protocol that efficiently evaluates the methylation status of LINE-1s; the method is referred to as PCR “COBRALINE-1”. This article reviewed what have been learned by applying this technique to study methylation level of repetitive sequences from several sources of genomic DNA. Results: We have found that LINE-1 methylation patterns among normal tissues are distinct. Therefore, this epigenetic event may be continuously altered in adult tissues by the process of cellular differentiation. Moreover, we confirmed that global hypomethylation is an ongoing process that develops during tumor progression, in addition to previous evidence of genomic and LINE-1 hypomethylation occurring as an early event in carcinogenesis. COBRALINE-1 is a highly effective technique for evaluating the genome-wide level of methylation, in particular from tissue samples with minute amounts of low quality DNA. The technique has been applied to study samples from micro-dissected archived paraffin-embedded tissues and sera of several types of cancer. Conclusion: The COBRALINE-1 technique demonstrated its potential to be a tumor marker and a great tool to explore the biology of global hypomethylation.
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Many carcinomas have an active mononuclear cell infiltrates surrounding tumor. Various in vitro assays have shown that cellular constituents of peripheral blood mononuclear cells(PBMC) can alter growth of carcinoma cell line. Author compared the effects of normal fibroblasts on squamous cell carcinoma cell line(SCL-1) along with those of sctivated and/or nonactivated PBMC on SCI 1 using a skin equivalent system. This system prevents direct cellular contact by growing SCL-1 on an overlying Millicell-HA membrane and normal fibroblast or supernatants of PBMC in a lower chamber. Normal fibroblasts enhanced the outgrowth of SCL-1 and induced a more organized phenotype of SCL-1. Supernatants from nonstimulated PBMC suppressed outgrowth of SCL 1, and concanavalin A stimulated PBMC supernatants alterd rnorphology of cultured SCL-1 from a disorganized phenotype to a more organized phenotype. It is concluded that fibroblasts and PBMC may affect the growth and differentiation of SCL-1 via their mediators(cytokines)