Alternative Splicing and Nonsense-Mediated RNA Decay Contribute to the Regulation of SHOX Expression

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 specif...

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Vydáno v:	PloS one Ročník 6; číslo 3; s. e18115
Hlavní autoři:	Durand, Claudia, Roeth, Ralph, Dweep, Harsh, Vlatkovic, Irena, Decker, Eva, Schneider, Katja Ute, Rappold, Gudrun
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 23.03.2011 Public Library of Science (PLoS)
Témata:	3' Untranslated regions Alternative splicing Alternative Splicing - genetics Binding Sites Biology Biosynthesis Bone growth Brain Codon, Nonsense - genetics Decay Deoxyribonucleic acid DNA Embryos Exons Exons - genetics Experiments Fetuses Fibroblasts Functional analysis Gene expression Genes Genetic disorders Genomics Homeobox Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Human tissues Humans Isoforms MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism miRNA Mutation Osteogenesis Polymerase chain reaction Protein Isoforms - genetics Protein Isoforms - metabolism Regulatory mechanisms (biology) Ribonucleic acid RNA RNA sequencing RNA Stability - genetics RNA, Messenger - genetics RNA, Messenger - metabolism Short Stature Homeobox Protein Tissues Transcription (Genetics) Transcription factors Germany
ISSN:	1932-6203, 1932-6203
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Shrnutí:	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 3'UTR exons yielded insights into the putative role of the different 3'UTRs as targets for miRNA binding. Functional analysis revealed that inclusion of exon 2a leads to nonsense-mediated RNA decay altering SHOX expression in a tissue and time specific manner. In conclusion, SHOX expression is regulated by different mechanisms and alternative splicing coupled with nonsense-mediated RNA decay constitutes a further component that can be used to fine tune the SHOX expression level.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 Conceived and designed the experiments: CD GR. Performed the experiments: CD RR IV. Analyzed the data: CD RR IV HD GR. Contributed reagents/materials/analysis tools: IV HD. Wrote the paper: CD GR. Provided input into the project's direction: ED KUS.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0018115