Adenosine-to-inosine RNA editing is essential to prevent undesired immune activation. This diverse process alters the genetic content of the RNA and may recode proteins, change splice sites and miRNA targets, and mimic genomic mutations. Recent studies have associated or implicated aberrant editing with pathological conditions, including cancer, autoimmune diseases, and neurological and psychiatric conditions. RNA editing patterns in cardiovascular tissues have not been investigated systematically so far, and little is known about its potential role in cardiac diseases. Some hints suggest robust editing in this system, including the fact that ADARB1 (ADAR2), the main coding-sequence editor, is most highly expressed in these tissues. Here we characterized RNA editing in the heart and arteries and examined a contributory role to the development of atherosclerosis and two structural heart diseases -Ischemic and Dilated Cardiomyopathies. Analyzing hundreds of RNA-seq samples taken from the heart and arteries of cardiac patients and controls, we find that global editing, alongside inflammatory gene expression, is increased in patients with atherosclerosis, cardiomyopathies, and heart failure. We describe a single recoding editing site and suggest it as a target for focused research. This recoding editing site in the IGFBP7 gene is one of the only evolutionary conserved sites between mammals, and we found it exhibits consistently increased levels of editing in these patients. Our findings reveal that RNA editing is abundant in arteries and is elevated in several key cardiovascular conditions. They thus provide a roadmap for basic and translational research of RNA as a mediator of atherosclerosis and non-genetic cardiomyopathies.

Bioinformatics (2009) doi:10.1093/bioinformatics/btp031 The following funding acknowledgement was omitted from the above paper: This research was supported in part by the Division of Intramural Research, NICHD, National Institutes of Health. The authors apologize for this error which has been corrected online.

Abstract Summary: DREAM: detecting RNA editing associated with microRNAs, is a webserver for the identification of mature microRNA editing events using deep sequencing data. Raw microRNA sequencing reads can be provided as input, the reads are aligned against the genome and custom scripts process the data, search for potential editing sites and assess the statistical significance of the findings. The output is a text file with the location and the statistical description of all the putative editing sites detected. Availability and implementation: DREAM is freely available on the web at http://www.cs.tau.ac.il/∼mirnaed/. Contact: [email protected]

MOTIVATION: The identification of functional cis-acting DNA regulatory elements is a crucial step towards understanding gene regulation. Ab initio motif detection algorithms have been extensively used in search of regulatory elements. Yet, their success in providing experimentally validated regulatory elements in vertebrates has been limited. RESULTS: Here we report in silico identification and in vivo validation of regulatory elements that determine enhanced gene expression in the pineal gland of zebrafish. Microarray data enabled detection of genes that exhibit high expression in the pineal gland. The promoter regions of these genes were computationally analyzed in order to identify overrepresented motifs. The highest ranking motif identified is a CRX/OTX binding site, known to govern expression in the pineal gland and retina. The second highest ranking motif was not reported before; we experimentally validated its function in vivo by mutational analysis. The methodology presented here may be applicable as a general scheme for finding regulatory elements that contribute to tissue-specific gene expression.