Triadin-Antisense: An lncRNA in the Backstage of Cardiac Alternative Splicing

Montañés-Agudo, Pablo; Pinto, Yigal M.

doi:10.1161/circulationaha.122.061232

Cited by 2 publications

(1 citation statement)

References 16 publications

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“…LncRNAs add another layer of complexity to the highly orchestrated splicing process. Alternative splicing of mRNAs and lncRNAs may lead to the creation of alternative lncRNA transcripts which differentially regulated cellular pathways, which might contribute to diseases like cancer or cardiovascular diseases 77,78 . Conversely, lncRNAs can modulate splicing of pre-mRNA in different ways as illustrated in 79 .…”

Section: Lncrnas Are Subjects and Mediators Of Asmentioning

confidence: 99%

The endothelial-specific highly expressed long non-coding RNA LINC00607 governs the endothelial phenotype

Lam

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Sprache Englisch The role of lncRNAs in the CVS and the endothelium is highly diverse and has been subject to a substantial amount of research over the last decade. The identification of lncRNAs as clinically relevant biomarkers and as co-regulatory molecules let to the appreciation of the functional relevance of lncRNAs. In the present study, LINC00607 was identified as an endothelial-enriched, human-specific lncRNA. With its distinct functions, LINC00607 maintains and supports the endothelial homeostasis especially in response to VEGF-A signalling. In the first part of this study, LINC00607 was functionally characterized in human endothelial cells. LINC00607 is highly and specifically expressed in endothelial cells and is differentially regulated in CVDs. Depletion of LINC00607 resulted in decreased angiogenic sprouting, reduced integration of ECs in a newly formed vascular network in vivo, enhanced endothelial migration and differential expression of many important genes for endothelial cell homeostasis. Functionally, LINC00607 maintains ERG-driven endothelial gene expression programs through BRG1. BRG1 secures stably accessible enhancer regions as well as TSS of ERG target genes, thus enabling transcription of endothelial gene programs. The second part of this study proposes an additional mode of action for LINC00607. The strongly impaired response to VEGF-A after LINC00607 KO can only be partially explained by its’ expression control of ERG target genes. It rather appears that LINC00607 is involved in the control of alternative splicing of VEGF receptor FLT1. The differential splicing of FLT1 produces the anti-angiogenic soluble isoform of FLT1. Even though further validation is needed to uncover the underlying mechanism, there is the potential of a more general role of LINC00607 in splicing control through BRG1. As AS of FLT1 is a clinical marker in preeclampsia, LINC00607 might qualify to be an additional marker for the onset and manifestation of the pregnancy disorder. Taken together, LINC00607 is a target in future for molecular therapy in CVD to restore a healthy endothelial phenotype and has the potential to serve as a biomarker in preeclampsia.

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Section: Lncrnas Are Subjects and Mediators Of Asmentioning

confidence: 99%