Circulating microRNAs (miRNAs) have emerged as novel biomarkers of diabetes. The current study focuses on the role of circulating miRNAs in patients with type 1 diabetes and their association with diabetic retinopathy. A total of 29 miRNAs were quantified in serum samples (n = 300) using a nested case-control study design in two prospective cohorts of the DIabetic REtinopathy Candesartan Trial (DIRECT): PROTECT-1 and PREVENT-1. The PREVENT-1 trial included patients without retinopathy at baseline; the PROTECT-1 trial included patients with nonproliferative retinopathy at baseline. Two miRNAs previously implicated in angiogenesis, miR-27b and miR-320a, were associated with incidence and with progression of retinopathy: the odds ratio per SD higher miR-27b was 0.57 (95% CI 0.40, 0.82; P = 0.002) in PREVENT-1, 0.78 (0.57, 1.07; P = 0.124) in PROTECT-1, and 0.67 (0.50, 0.92; P = 0.012) combined. The respective odds ratios for higher miR-320a were 1.57 (1.07, 2.31; P = 0.020), 1.43 (1.05, 1.94; P = 0.021), and 1.48 (1.17, 1.88; P = 0.001). Proteomics analyses in endothelial cells returned the antiangiogenic protein thrombospondin-1 as a common target of both miRNAs. Our study identifies two angiogenic miRNAs, miR-320a and miR-27b, as potential biomarkers for diabetic retinopathy.Recent studies have begun to unveil a powerful and unexpected role of microRNAs (miRNAs) in numerous forms of diseases, providing a unique opportunity to translate this knowledge into the clinical setting in the form of miRNA-based therapeutics and diagnostics (1,2). miRNAs are small noncoding RNAs with cell-type specific expression patterns that orchestrate biological networks by modulating gene expression. miRNAs form base pairs with their target messenger RNAs and mediate gene silencing, often regulating multiple proteins within the same biological pathways. Given their importance in angiogenesis, along with the technical feasibility in manipulating their function in vivo, vascular miRNAs have become central targets for therapeutic manipulation, including diabetes (3).Additionally, miRNAs circulate in blood. We have previously performed the first systematic analysis of circulating miRNAs in a population-based study (the Bruneck Study) and identified distinct miRNA signatures associated with type 2 diabetes (4) and risk of myocardial infarction (5). We have also highlighted their platelet origin (6) and applied concepts of network topology to explore their biomarker potential (7). Exciting opportunities exist to pursue miRNAs as novel biomarkers for risk estimation and patient stratification (8).The current study addresses the role of circulating miRNAs in patients with type 1 diabetes (T1D) and their association with microvascular complications, in particular, diabetic retinopathy. Our aims were threefold: first, to evaluate whether miRNA profiles are independently associated with retinopathy development and progression in diabetes; second, to quantify the incremental discriminatory power of miRNAs over and above traditional risk markers; ...

Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During differentiation, cells acquire distinct epigenetic landscapes, which determine their function, however the mechanisms which regulate this are poorly understood. The demethylation of 5-methylcytosine (5mC) is achieved via successive oxidation reactions catalysed by the Ten-Eleven-Translocation (Tet) enzymes, yielding the 5-hydroxymethylcytosine (5hmC) intermediate. These require O2 as a co-factor, and hence may link epigenetic processes directly to O2 gradients during development. We demonstrate that the activities of Tet enzymes display distinct patterns of [O2]-dependency, and that Tet1 activity, specifically, is subject to differential regulation within a range of O2 which is physiologically relevant in embryogenesis. Further, differentiating embryonic stem cells displayed a transient burst of 5hmC, which was both dependent upon Tet1 and inhibited by low (1%) [O2]. A GC-rich promoter region within the Tet3 locus was identified as a significant target of this 5mC-hydroxylation. Further, this region was shown to associate with Tet1, and display the histone epigenetic marks, H3K4me3 and H3K27me3, which are characteristic of a bivalent, developmentally ‘poised’ promoter. We conclude that Tet1 activity, determined by [O2] may play a critical role in regulating cellular differentiation and fate in embryogenesis.

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