Discriminative prediction of A-To-I RNA editing events from DNA sequence

RNA editing is a post-transcriptional alteration of RNA sequences that, via insertions, deletions or base substitutions, can affect protein structure as well as RNA and protein expression. Recently, it has been suggested that RNA editing may be more frequent than previously thought. A great impediment, however, to a deeper understanding of this process is the paramount sequencing effort that needs to be undertaken to identify RNA editing events. Here, we describe an in silico approach, based on machine learning, that ameliorates this problem. Using 41 nucleotide long DNA sequences, we show that novel A-to-I RNA editing events can be predicted from known A-to-I RNA editing events intra- and interspecies. The validity of the proposed method was verified in an independent experimental dataset. Using our approach, 203 202 putative A-to-I RNA editing events were predicted in the whole human genome. Out of these, 9% were previously reported. The remaining sites require further validation, e.g., by targeted deep sequencing. In conclusion, the approach described here is a useful tool to identify potential A-to-I RNA editing events without the requirement of extensive RNA sequencing

Fetal PGC-1 alpha Overexpression Programs Adult Pancreatic beta-Cell Dysfunction

International audienceAdult beta-cell dysfunction, a hallmark of type 2 diabetes, can be programmed by adverse fetal environment. We have shown that fetal glucocorticoids (GCs) participate in this programming through inhibition of beta-cell development. Here we have investigated the molecular mechanisms underlying this regulation. We showed that GCs stimulate the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), a coregulator of the GCs receptor (GR), and that the overexpression of PGC-1 alpha represses genes important for beta-cell development and function. More precisely, PGC-1 alpha inhibited the expression of the key beta-cell transcription factor pancreatic duodenal homeobox 1 (Pdx1). This repression required the GR and was mediated through binding of a GR/PGC-1 alpha complex to the Pdx1 promoter. To explore PGC-1 alpha function, we generated mice with inducible beta-cell PGC-1 alpha overexpression. Mice overexpressing PGC-1 alpha exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased beta-cell mass, and beta-cell hypotrophy. Interestingly, PGC-1 alpha expression in fetal life only was sufficient to impair adult beta-cell function whereas beta-cell PGC-1 alpha overexpression from adult age had no consequence on beta-cell function. Altogether, our results demonstrate that the GR and PGC-1 alpha participate in the fetal programming of adult beta-cell function through inhibition of Pdx1 expression. Diabetes 62:1206-1216, 201