Abstract
The role and function of long non-coding RNAs (lncRNAs) in modulating gene expression is becoming apparent. Vascular endothelial growth factor A (VEGF-A) is a key regulator of blood vessel formation and maintenance making it a promising therapeutic target for activation in ischemic diseases. In this study, we uncover a functional role for two antisense VEGF-A lncRNAs, RP1-261G23.7 and EST AV731492, in transcriptional regulation of VEGF-A during hypoxia. We find here that both lncRNAs are polyadenylated, concordantly upregulated with VEGF-A, localize to the VEGF-A promoter and upstream elements in a hypoxia dependent manner either as a single-stranded RNA or DNA bound RNA, and are associated with enhancer marks H3K27ac and H3K9ac. Collectively, these data suggest that VEGF-A antisense lncRNAs, RP1-261G23.7 and EST AV731492, function as VEGF-A promoter enhancer-like elements, possibly by acting as a local scaffolding for proteins and also small RNAs to tether.
Highlights
Over the last decade, the role of non-coding transcripts, both long and short forms, in controlling transcriptional and epigenetic states has become realized
We focused here on interrogating the function of two antisense long non-coding RNAs (lncRNAs) that are associated with the vascular endothelial growth factor A (VEGF-A) promoter and upstream elements
In this study, we identified a sense transcript at the VEGF-AS2 locus that is responsive to hypoxia
Summary
The role of non-coding transcripts, both long and short forms, in controlling transcriptional and epigenetic states has become realized (reviewed in [1,2]). Small RNA directed transcriptional activation has previously been observed with vascular endothelial growth factor A (VEGF-A) [4,5,6,7] and appears to be the result of the small RNA interacting with sense or antisense non-coding transcripts at the VEGF-A promoter [8]. It appears that the small RNAs interact with transcripts at the targeted promoter to imbue the recruitment of various epigenetic remodeling complexes, resulting in transcriptional gene silencing or activation (reviewed in [9,10]). We find here that VEGF-A and the VEGF-A associated antisense transcripts are concordantly linked and that the antisense transcripts function locally at the promoter as enhancer elements to modify VEGF-A expression
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