alternative splicing and nonsense-mediated rna decay contribute to the regulation of shox expression可变剪接和nonsense-mediated rna衰变为减震器的规定表达.pdfVIP

Alternative Splicing and Nonsense-Mediated RNA Decay Contribute to the Regulation of SHOX Expression 1 1 2 3 1 1 Claudia Durand , Ralph Roeth , Harsh Dweep , Irena Vlatkovic , Eva Decker , Katja Ute Schneider , Gudrun Rappold1* 1 Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany, 2 Medical Research Center, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany, 3 Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria Abstract The human SHOX gene is composed of seven exons and encodes a paired-related homeodomain transcription factor. SHOX mutations or deletions have been associated with different short stature syndromes implying a role in growth and bone formation. During development, SHOX is expressed in a highly specific spatiotemporal expression pattern, the underlying regulatory mechanisms of which remain largely unknown. We have analysed SHOX expression in diverse embryonic, fetal and adult human tissues and detected expression in many tissues that were not known to express SHOX before, e.g. distinct brain regions. By using RT-PCR and comparing the results with RNA-Seq data, we have identified four novel exons (exon 2a, 7-1, 7-2 and 7-3) contributing to different SHOX isoforms, and also established an expression profile for the emerging new SHOX isoforms. Interestingly, we found the exon 7 variants to be exclusively expressed in fetal neural tissues, which could argue for a specific role of these variants during brain development. A bioinformatical analysis of the three novel 39UTR exons yielded insights into the putative role of the different 39UTRs as targets for miRNA binding. Functional analysis revealed that inclusion of