Regulation of Rac1 transcription by histone and DNA methylation in diabetic retinopathy

Abstract Cytosolic ROS, generated by NADPH oxidase 2 (Nox2) in diabetes, damage retinal mitochondria, which leads to the development of retinopathy. A small molecular weight G-protein essential for Nox2 activation, Rac1, is also transcriptionally activated via active DNA methylation-hydroxymethylati...

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Autores principales:	Renu A. Kowluru, Rakesh Radhakrishnan, Ghulam Mohammad
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ecd9541b00b64777b0106355a4ab418b
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spelling	oai:doaj.org-article:ecd9541b00b64777b0106355a4ab418b2021-12-02T15:39:41ZRegulation of Rac1 transcription by histone and DNA methylation in diabetic retinopathy10.1038/s41598-021-93420-42045-2322https://doaj.org/article/ecd9541b00b64777b0106355a4ab418b2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93420-4https://doaj.org/toc/2045-2322Abstract Cytosolic ROS, generated by NADPH oxidase 2 (Nox2) in diabetes, damage retinal mitochondria, which leads to the development of retinopathy. A small molecular weight G-protein essential for Nox2 activation, Rac1, is also transcriptionally activated via active DNA methylation-hydroxymethylation. DNA methylation is a dynamic process, and can also be regulated by histone modifications; diabetes alters retinal histone methylation machinery. Our aim is to investigate the role of histone methylation (H3K9me3) of Rac1 promoter in dynamic DNA methylation- transcriptional activation. Using human retinal endothelial cells in 20 mM D-glucose, H3K9me3 at Rac1 promoter was quantified by chromatin-Immunoprecipitation technique. Crosstalk between H3K9me3 and DNA methylation was examined in cells transfected with siRNA of histone trimethyl-transferase, Suv39H1, or Dnmt1, exposed to high glucose. Key parameters were confirmed in retinal microvessels from streptozotocin-induced diabetic mice, with intravitreally administered Suv39H1-siRNA or Dnmt1-siRNA. Compared to cells in normal glucose, high glucose increased H3K9me3 and Suv39H1 binding at Rac1 promoter, and Suv39H1-siRNA prevented glucose-induced increase 5 hydroxy methyl cytosine (5hmC) and Rac1 mRNA. Similarly, in diabetic mice, Suv39H1-siRNA attenuated increase in 5hmC and Rac1 mRNA. Thus, H3K9me3 at Rac1 promoter assists in active DNA methylation-hydroxymethylation, activating Rac1 transcription. Regulation of Suv39H1-H3K9 trimethylation could prevent further epigenetic modifications, and prevent diabetic retinopathy.Renu A. KowluruRakesh RadhakrishnanGhulam MohammadNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Renu A. Kowluru Rakesh Radhakrishnan Ghulam Mohammad Regulation of Rac1 transcription by histone and DNA methylation in diabetic retinopathy
description	Abstract Cytosolic ROS, generated by NADPH oxidase 2 (Nox2) in diabetes, damage retinal mitochondria, which leads to the development of retinopathy. A small molecular weight G-protein essential for Nox2 activation, Rac1, is also transcriptionally activated via active DNA methylation-hydroxymethylation. DNA methylation is a dynamic process, and can also be regulated by histone modifications; diabetes alters retinal histone methylation machinery. Our aim is to investigate the role of histone methylation (H3K9me3) of Rac1 promoter in dynamic DNA methylation- transcriptional activation. Using human retinal endothelial cells in 20 mM D-glucose, H3K9me3 at Rac1 promoter was quantified by chromatin-Immunoprecipitation technique. Crosstalk between H3K9me3 and DNA methylation was examined in cells transfected with siRNA of histone trimethyl-transferase, Suv39H1, or Dnmt1, exposed to high glucose. Key parameters were confirmed in retinal microvessels from streptozotocin-induced diabetic mice, with intravitreally administered Suv39H1-siRNA or Dnmt1-siRNA. Compared to cells in normal glucose, high glucose increased H3K9me3 and Suv39H1 binding at Rac1 promoter, and Suv39H1-siRNA prevented glucose-induced increase 5 hydroxy methyl cytosine (5hmC) and Rac1 mRNA. Similarly, in diabetic mice, Suv39H1-siRNA attenuated increase in 5hmC and Rac1 mRNA. Thus, H3K9me3 at Rac1 promoter assists in active DNA methylation-hydroxymethylation, activating Rac1 transcription. Regulation of Suv39H1-H3K9 trimethylation could prevent further epigenetic modifications, and prevent diabetic retinopathy.
format	article
author	Renu A. Kowluru Rakesh Radhakrishnan Ghulam Mohammad
author_facet	Renu A. Kowluru Rakesh Radhakrishnan Ghulam Mohammad
author_sort	Renu A. Kowluru
title	Regulation of Rac1 transcription by histone and DNA methylation in diabetic retinopathy
title_short	Regulation of Rac1 transcription by histone and DNA methylation in diabetic retinopathy
title_full	Regulation of Rac1 transcription by histone and DNA methylation in diabetic retinopathy
title_fullStr	Regulation of Rac1 transcription by histone and DNA methylation in diabetic retinopathy
title_full_unstemmed	Regulation of Rac1 transcription by histone and DNA methylation in diabetic retinopathy
title_sort	regulation of rac1 transcription by histone and dna methylation in diabetic retinopathy
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ecd9541b00b64777b0106355a4ab418b
work_keys_str_mv	AT renuakowluru regulationofrac1transcriptionbyhistoneanddnamethylationindiabeticretinopathy AT rakeshradhakrishnan regulationofrac1transcriptionbyhistoneanddnamethylationindiabeticretinopathy AT ghulammohammad regulationofrac1transcriptionbyhistoneanddnamethylationindiabeticretinopathy
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Regulation of Rac1 transcription by histone and DNA methylation in diabetic retinopathy

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