The lncRNA GATA6-AS epigenetically regulates endothelial gene expression via interaction with LOXL2

Neumann, Philipp; Jaé, Nicolas; Knau, Andrea; Glaser, Simone F.; Fouani, Youssef; Roßbach, Oliver; Krüger, Marcus; John, David; Bindereif, Albrecht; Grote, Phillip; Boon, Reinier A.; Dimmeler, Stefanie

doi:10.1038/s41467-017-02431-1

Cited by 154 publications

(144 citation statements)

References 71 publications

(64 reference statements)

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“…Protein levels are expressed as a ratio to β-actin (mean ± SD); *p<0.05 vs empty vector treated with NG; † p<0.05 vs empty vector treated with HG. n=6 per group except for western blots, which were n=3 per group study has revealed that hypoxia-induced EndMT in human umbilical vein endothelial cells was promoted by the lncRNA GATA6-AS, through histone methylation [42]. Nevertheless, the role of lncRNAs in regulating hyperglycaemia-induced EndMT remains unclear.…”

Section: Discussionmentioning

confidence: 99%

lncRNA H19 prevents endothelial–mesenchymal transition in diabetic retinopathy

et al. 2019

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Aims/hypothesis The pathophysiology of diabetic retinopathy is linked to hyperglycaemia and its effect on retinal microvascular tissues. The resulting endothelial injury changes the endothelial cell phenotype to acquire mesenchymal properties (i.e. endothelial-mesenchymal transition [EndMT]). Such changes can be regulated by epigenetic mechanisms, including long non-coding RNAs (lncRNAs). lncRNA H19 may influence EndMT through TGF-β. We investigated the role of H19 in regulating EndMT during diabetic retinopathy. Methods H19 was overexpressed or silenced in human retinal endothelial cells exposed to various glucose levels. The cells were examined for H19, endothelial and mesenchymal markers. We then expanded the study to retinal tissues in a mouse model of diabetic retinopathy and also examined vitreous humour samples from individuals with proliferative diabetic retinopathy. Results Expression of H19 was downregulated in high glucose conditions (25 mmol/l). H19 overexpression prevented glucoseinduced EndMT. Such changes appear to involve TGF-β through a Smad-independent mechanism. Diabetes caused downregulation of retinal H19. Using H19 knockout mice, we demonstrated similar EndMT in the retina. Examination of vitreous humour from individuals with proliferative diabetic retinopathy also reinforced the downregulation of H19 in diabetes. Conclusions/interpretationWe therefore concluded that H19 regulates EndMT in diabetic retinopathy through specific mechanisms. Data availability The results from our previous microarray can be found online using the GEO accession number GSE122189.

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Section: Discussionmentioning

confidence: 99%

lncRNA H19 prevents endothelial–mesenchymal transition in diabetic retinopathy

et al. 2019

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“…LincRNAs function to control gene expression either in cis, where they influence the expression and/or chromatin state of neighboring genes, or in trans, where the lincRNA leaves the site of transcription and affects genes on different chromosomes (Kopp and Mendell, 2018; Liang et al, 2018; Neumann et al, 2018). These trans -acting lincRNAs, such as FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR), long-intergenic non-coding-erythroid prosurvival (linc-EPS), and Nettoie Salmonella pasTheiler’s (NeST), can function to regulate chromatin states (Atianand et al, 2016; Gomez et al, 2013; Grote et al, 2013; Sauvageau et al, 2013), influence nuclear structure and organization (Rinn and Guttman, 2014), or interact with and regulate the behavior of proteins and/or other RNA molecules (Covarrubias et al, 2017; Kawasaki et al, 2018; Lee et al, 2016; Wang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Genetic Models Reveal cis and trans Immune-Regulatory Activities for lincRNA-Cox2

et al. 2018

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SUMMARY An inducible gene expression program is a hallmark of the host inflammatory response. Recently, long intergenic non-coding RNAs (lincRNAs) have been shown to regulate the magnitude, duration, and resolution of these responses. Among these is lincRNA- Cox2, a dynamically regulated gene that broadly controls immune gene expression. To evaluate the in vivo functions of this lincRNA, we characterized multiple models of lincRNA-Cox2-deficient mice. LincRNA- Cox2-deficient macrophages and murine tissues had altered expression of inflammatory genes. Tran- scriptomic studies from various tissues revealed that deletion of the lincRNA-Cox2 locus also strongly impaired the basal and inducible expression of the neighboring gene prostaglandin-endoperoxide synthase (Ptgs2), encoding cyclooxygenase-2, a key enzyme in the prostaglandin biosynthesis pathway. By utilizing different genetic manipulations in vitro and in vivo, we found that lincRNA-Cox2 functions through an enhancer RNA mechanism to regulate Ptgs2. More importantly, lincRNA-Cox2 also functions in trans, independently of Ptgs2, to regulate critical innate immune genes in vivo.

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“…This suggests a specific role of activation of promoter activity of lncRNAs in hNPCs differentiation. Divergent lncRNAs have earlier been shown to have a role in both activations as well as suppression of coding gene transcription [35]. Further, to understand the impact of epigenetics on DELs, we studied the number of DELs showing the presence of epigenetic markers on their promoters.…”

Section: Discussionmentioning

confidence: 99%

Identification and epigenetic analysis of divergent long non-coding RNAs in multilineage differentiation of human Neural Progenitor Cells

et al. 2018

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2019) Identification and epigenetic analysis of divergent long non-coding RNAs in multilineage differentiation of human Neural Progenitor Cells, RNA Biology, 16:1, 13-24, ABSTRACT Long non-coding RNAs have emerged as an important regulatory layer in biological systems. Of the various types of lncRNAs, one class (designated as divergent RNAs/XH), which is in head-to-head overlap with the coding genes, has emerged as a critical biotype that regulates development and cellular differentiation. This work aimed to analyze previously published data on differential expression, epigenetic and network analysis in order to demonstrate the association of divergent lncRNAs, a specific biotype with the differentiation of human neural progenitor cells (hNPCs). We have analyzed various available RNAseq databases that address the neuronal and astrocytic differentiation of hNPCs and identified differentially expressed lncRNAs (DELs) during cell-fate determination. Key DELs identified from the databases were experimentally verified by us in our in-vitro hNPC differentiation system. We also analyzed the change in promoter activity using ChIP-seq datasets of the histone markers H3K4me3 (activation) and H3K27me3 (inactivation) of these DELs. Additionally, we explored the change in the euchromatinization state of DELs (by analyzing DNase-seq data) during lineage-specific differentiation of hNPCs and performed their network analysis. We were able to identify differences between neuronal and astrocytic differentiation of hNPCs at the level of divergent DELs epigenetic markers, DNAase hypersensitive sites and gene expression network. Divergent lncRNAs are more involved in neuronal rather than astrocytic differentiation, while the sense downstream lncRNA biotype appears to be more involved in astrocytic differentiation. By studying the lncRNA involvement of distinct biotypes, we have been able to indicate the preferential role of a particular biotype during lineage-specific differentiation. ARTICLE HISTORY

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The lncRNA GATA6-AS epigenetically regulates endothelial gene expression via interaction with LOXL2

Cited by 154 publications

References 71 publications

lncRNA H19 prevents endothelial–mesenchymal transition in diabetic retinopathy

lncRNA H19 prevents endothelial–mesenchymal transition in diabetic retinopathy

Genetic Models Reveal cis and trans Immune-Regulatory Activities for lincRNA-Cox2

Identification and epigenetic analysis of divergent long non-coding RNAs in multilineage differentiation of human Neural Progenitor Cells

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