Abstract
Previous studies proposed the application of DNA methylation signatures as clinical biomarkers of age-related macular degeneration (AMD). However, the characterization of Long Interspersed Nuclear Element-1 (LINE-1) methylation levels—a surrogate marker of global DNA methylation—in AMD patients has not been investigated so far. In the present study, we first characterized DNA methyltransferases (DNMTs) and Sirtuin 1 (SIRT1) functions in blood samples of 40 AMD patients and 10 age- and sex-matched controls. Then, we evaluated whether changes in DNMTs functions were associated with different LINE-1 methylation levels in leukocyte DNA. We demonstrated that total DNMTs activity was 48% higher in AMD patients than in controls (p = 0.005). AMD patients also exhibited up-regulation of DNMT1 and DNMT3B expression (FC = 2.6; p = 0.003 and FC = 2.4; p = 0.018, respectively). In line with increased DNMTs functions, the LINE-1 methylation level was higher in AMD patients than in controls (mean = 69.10%; SE = 0.68 vs. mean = 65.73%; SE = 0.59; p = 0.020). All p-values were adjusted by Bonferroni correction. In AMD patients, LINE-1 methylation level was positively associated with total DNMTs activity (r = 0.694; p < 0.001), DNMT1 (r = 0.579; p < 0.001), and DNMT3B (r = 0.521; p = 0.001) expression. Our results encourage further large-size prospective research to understand the relationship between LINE-1 methylation and AMD aetiology, and its usefulness in the clinical setting.
Highlights
Age-related macular degeneration (AMD) is a neurodegenerative disease that leads to the progressive destruction of the neurosensory macular area, involving retinal pigment epithelium (RPE), Bruch’s membrane and choroid [1]
While the early stage is characterized by the aberrant pigmentation of the RPE and the accumulation of “drusen”, the advanced stage may manifest as non-exudative or exudative AMD
In line with the hypothesis that global DNA methylation might be modulated by a DNA methyltransferases (DNMTs)-dependent pathway, we demonstrated that Long Interspersed Nuclear Element-1 (LINE-1) methylation level was higher in blood leukocyte DNA of AMD patients than in healthy controls
Summary
Age-related macular degeneration (AMD) is a neurodegenerative disease that leads to the progressive destruction of the neurosensory macular area, involving retinal pigment epithelium (RPE), Bruch’s membrane and choroid [1]. Several lines of evidence suggest a possible role for epigenetic changes—including DNA methylation, histone modification, and expression of non-coding RNA—in. Aberrant epigenetic patterns have been described in several pathophysiological processes—such as aging, oxidative stress, inflammation, and angiogenesis—that are related to the pathogenesis of retinal degenerative diseases [4,5,6,7]. Long Interspersed Nuclear Element-1 (LINE-1) sequences, accounting for ≈18% of human genome, have been widely used as a surrogate marker of global methylation in aging and age-related disease [12,13,14,15]. In the context of AMD, previous studies have focused on DNA methylation in genes involved in the etiology of the disease [16,17,18,19]. We evaluated whether changes in DNMTs functions were associated with different LINE-1 methylation levels in leukocyte DNA
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