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Polycomb repressive complex 2 regulates MiR-200b in retinal endothelial cells: potential relevance in diabetic retinopathy.

Ruiz MA, Feng B, Chakrabarti S - PLoS ONE (2015)

Bottom Line: Histone methyltransferase complex, Polycomb Repressive Complex 2 (PRC2), has been shown to repress miRNAs in neoplastic process.We show that human retinal microvascular endothelial cells exposed to high levels of glucose regulate miR-200b repression through histone methylation and that inhibition of PRC2 increases miR-200b while reducing VEGF.This research established a repressive relationship between PRC2 and miR-200b, providing evidence of a novel mechanism of miRNA regulation through histone methylation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.

ABSTRACT
Glucose-induced augmented vascular endothelial growth factor (VEGF) production is a key event in diabetic retinopathy. We have previously demonstrated that downregulation of miR-200b increases VEGF, mediating structural and functional changes in the retina in diabetes. However, mechanisms regulating miR-200b in diabetes are not known. Histone methyltransferase complex, Polycomb Repressive Complex 2 (PRC2), has been shown to repress miRNAs in neoplastic process. We hypothesized that, in diabetes, PRC2 represses miR-200b through its histone H3 lysine-27 trimethylation mark. We show that human retinal microvascular endothelial cells exposed to high levels of glucose regulate miR-200b repression through histone methylation and that inhibition of PRC2 increases miR-200b while reducing VEGF. Furthermore, retinal tissue from animal models of diabetes showed increased expression of major PRC2 components, demonstrating in vivo relevance. This research established a repressive relationship between PRC2 and miR-200b, providing evidence of a novel mechanism of miRNA regulation through histone methylation.

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Summary of key findings.(A) Glucose-induced increased PRC2 expression and activity causes alteration of miR-200b levels. Such changes may play a role in the development of diabetic retinopathy. (B) This relationship is regulated at the level of genome by PRC2-mediated repression through H3K27me3 at the miR-200b promoter region.
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pone.0123987.g007: Summary of key findings.(A) Glucose-induced increased PRC2 expression and activity causes alteration of miR-200b levels. Such changes may play a role in the development of diabetic retinopathy. (B) This relationship is regulated at the level of genome by PRC2-mediated repression through H3K27me3 at the miR-200b promoter region.

Mentions: In summary, we show that PRC2 regulates miR-200b in retinal endothelial cells through H3K27me3 repression (Fig 7). This is one of the first investigations to connect histone methylation and miRNA regulation in the context of diabetic retinopathy. Ultimately, this work builds on the characterization of miRNA our lab has studied by elucidating a new regulation mechanism. Investigating such mechanisms is important to further our understanding of the signaling events that occur in response to hyperglycemia in diabetic retinopathy, as well as developing novel treatment strategies to maintain the quality of life of patients with diabetes.


Polycomb repressive complex 2 regulates MiR-200b in retinal endothelial cells: potential relevance in diabetic retinopathy.

Ruiz MA, Feng B, Chakrabarti S - PLoS ONE (2015)

Summary of key findings.(A) Glucose-induced increased PRC2 expression and activity causes alteration of miR-200b levels. Such changes may play a role in the development of diabetic retinopathy. (B) This relationship is regulated at the level of genome by PRC2-mediated repression through H3K27me3 at the miR-200b promoter region.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401764&req=5

pone.0123987.g007: Summary of key findings.(A) Glucose-induced increased PRC2 expression and activity causes alteration of miR-200b levels. Such changes may play a role in the development of diabetic retinopathy. (B) This relationship is regulated at the level of genome by PRC2-mediated repression through H3K27me3 at the miR-200b promoter region.
Mentions: In summary, we show that PRC2 regulates miR-200b in retinal endothelial cells through H3K27me3 repression (Fig 7). This is one of the first investigations to connect histone methylation and miRNA regulation in the context of diabetic retinopathy. Ultimately, this work builds on the characterization of miRNA our lab has studied by elucidating a new regulation mechanism. Investigating such mechanisms is important to further our understanding of the signaling events that occur in response to hyperglycemia in diabetic retinopathy, as well as developing novel treatment strategies to maintain the quality of life of patients with diabetes.

Bottom Line: Histone methyltransferase complex, Polycomb Repressive Complex 2 (PRC2), has been shown to repress miRNAs in neoplastic process.We show that human retinal microvascular endothelial cells exposed to high levels of glucose regulate miR-200b repression through histone methylation and that inhibition of PRC2 increases miR-200b while reducing VEGF.This research established a repressive relationship between PRC2 and miR-200b, providing evidence of a novel mechanism of miRNA regulation through histone methylation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.

ABSTRACT
Glucose-induced augmented vascular endothelial growth factor (VEGF) production is a key event in diabetic retinopathy. We have previously demonstrated that downregulation of miR-200b increases VEGF, mediating structural and functional changes in the retina in diabetes. However, mechanisms regulating miR-200b in diabetes are not known. Histone methyltransferase complex, Polycomb Repressive Complex 2 (PRC2), has been shown to repress miRNAs in neoplastic process. We hypothesized that, in diabetes, PRC2 represses miR-200b through its histone H3 lysine-27 trimethylation mark. We show that human retinal microvascular endothelial cells exposed to high levels of glucose regulate miR-200b repression through histone methylation and that inhibition of PRC2 increases miR-200b while reducing VEGF. Furthermore, retinal tissue from animal models of diabetes showed increased expression of major PRC2 components, demonstrating in vivo relevance. This research established a repressive relationship between PRC2 and miR-200b, providing evidence of a novel mechanism of miRNA regulation through histone methylation.

Show MeSH
Related in: MedlinePlus