A noncoding antisense RNA in tie-1 locus regulates tie-1 function in vivo.
Recently, messenger RNAs in eukaryotes have shown to associate with antisense (AS) transcript partners that are often referred to as long noncoding RNAs (lncRNAs) whose function is largely unknown. Here, we have identified a natural AS transcript for tyrosine kinase containing immunoglobulin and epidermal growth factor homology domain-1 (tie-1), tie-1AS lncRNA in zebrafish, mouse, and humans. In embryonic zebrafish, tie-1AS lncRNA transcript is expressed temporally and spatially in vivo with its native target, the tie-1 coding transcript and in additional locations (ear and brain). The tie-1AS lncRNA selectively binds tie-1 mRNA in vivo and regulates tie-1 transcript levels, resulting in specific defects in endothelial cell contact junctions in vivo and in vitro. The ratio of tie-1 versus tie-1AS lncRNA is altered in human vascular anomaly samples. These results directly implicate noncoding RNA-mediated transcriptional regulation of gene expression as a fundamental control mechanism for physiologic processes, such as vascular development.
Li
Keguo
K
Department of Pediatrics, Medical College of Wisconsin, Developmental Vascular Biology Program, Children's Research Institute, Milwaukee, USA.
Blum
Yannick
Y
Verma
Anjali
A
Liu
Zhong
Z
Pramanik
Kallal
K
Leigh
Noah R
NR
Chun
Chang Z
CZ
Samant
Ganesh V
GV
Zhao
Baofeng
B
Garnaas
Maija K
MK
Horswill
Mark A
MA
Stanhope
Stephen A
SA
North
Paula E
PE
Miao
Robert Q
RQ
Wilkinson
George A
GA
Affolter
Markus
M
Ramchandran
Ramani
R
D000818:Animals; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D056426:Genetic Loci / Q000235:genetics*; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010641:Phenotype; D016372:RNA, Antisense / Q000235:genetics* / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism; D042810:Receptor, TIE-1 / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D014652:Vascular Diseases / Q000235:genetics / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D015027:Zebrafish / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D016372:RNA, Antisense; D022661:RNA, Untranslated; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; D042810:Receptor, TIE-1; C467973:tie1 protein, zebrafish