Glucose-induced, duration-dependent genome-wide DNA methylation changes in human endothelial cells

Aref‐Eshghi, Erfan; Biswas, Saumik; Chen, Charlie; Sadiković, Bekim; Chakrabarti, Subrata

doi:10.1152/ajpcell.00011.2020

Cited by 13 publications

(11 citation statements)

References 73 publications

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“…Methylation patterns of CpG sites across the HOTAIR gene were examined in HRECs using the Illumina Infinium Methy-lationEPIC BeadChip array (Illumina, Inc., San Diego, CA, USA), following the manufacturer's instructions and our previously published protocols (see Supplementary Materials). 16…”

Section: Methylation Analysis Of Cpg Sites Across Hotairmentioning

confidence: 99%

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The Long Non-Coding RNA HOTAIR Is a Critical Epigenetic Mediator of Angiogenesis in Diabetic Retinopathy

Biswas

Feng

Chen

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Diabetic retinopathy (DR) remains a pressing issue worldwide. Abnormal angiogenesis is a distinct vascular lesion in DR, and research has established that vascular endothelial growth factor A (VEGF-A) is a primary mediator of such changes. However, limitations in current anti-VEGF therapies suggest that our understanding of molecular networks underlying ocular angiogenesis remains far from complete. Based on our long non-coding RNA (lncRNA) array analyses, HOX antisense intergenic RNA (HOTAIR) was identified as one of the top upregulated lncRNAs in high glucose-cultured human retinal endothelial cells (HRECs). Given the well-documented roles of HOTAIR in cancer, no studies have examined the epigenetic implications of HOTAIR in DR, and we investigated such relationships herein. METHODS.We used HRECs exposed to various glucose concentrations and epigenetic modulators to examine HOTAIR, angiogenic, and DR-related molecular markers. Oxidative stress, angiogenesis, and mitochondrial dysfunction were assessed. Retinal tissues of diabetic rodents and the vitreous humor and serum of patients with proliferative DR were also investigated. RESULTS.Hyperglycemia significantly augmented HOTAIR expression in HRECs and promoted angiogenesis, oxidative damage, and mitochondrial aberrations. Similarly, vitreous humor and serum from proliferative DR patients and retinas from diabetic animals demonstrated increased HOTAIR expression compared to non-diabetic controls. HOTAIR knockdown protected against glucose-induced increases of angiogenic and diabetesassociated molecules in the retina. Mechanistically, we showed that HOTAIR exerts its capabilities by preventing oxidative stress and modulating epigenetic pathways involving histone methylation, histone acetylation, DNA methylation, and transcription factors. CONCLUSIONS.Our findings suggest that HOTAIR is a critical lncRNA in the pathogenesis of DR and may potentially be important for diagnostic and therapeutic targeting.

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Section: Methylation Analysis Of Cpg Sites Across Hotairmentioning

confidence: 99%

“…These findings suggest stable epigenetic DNA methylation across HOTAIR in HRECs during hyperglycemia. 16…”

Section: Glucose Does Not Cause Duration-dependent Cpg Methylation Almentioning

confidence: 99%

The Long Non-Coding RNA HOTAIR Is a Critical Epigenetic Mediator of Angiogenesis in Diabetic Retinopathy

Biswas

Feng

Chen

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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“…Recently, the effect of glucose on whole genome DNA methylation was studied in human retinal endothelial cells and HUVECs [165]. The lines were exposed to basal (5 mmol/L) or high (25 mmol/L) glucose-containing media for variable lengths of time.…”

Section: Epigenetic Modificationsmentioning

confidence: 99%

Glucose Variability: How Does It Work?

Климонтов

Saik

Korbut

2021

IJMS

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A growing body of evidence points to the role of glucose variability (GV) in the development of the microvascular and macrovascular complications of diabetes. In this review, we summarize data on GV-induced biochemical, cellular and molecular events involved in the pathogenesis of diabetic complications. Current data indicate that the deteriorating effect of GV on target organs can be realized through oxidative stress, glycation, chronic low-grade inflammation, endothelial dysfunction, platelet activation, impaired angiogenesis and renal fibrosis. The effects of GV on oxidative stress, inflammation, endothelial dysfunction and hypercoagulability could be aggravated by hypoglycemia, associated with high GV. Oscillating hyperglycemia contributes to beta cell dysfunction, which leads to a further increase in GV and completes the vicious circle. In cells, the GV-induced cytotoxic effect includes mitochondrial dysfunction, endoplasmic reticulum stress and disturbances in autophagic flux, which are accompanied by reduced viability, activation of apoptosis and abnormalities in cell proliferation. These effects are realized through the up- and down-regulation of a large number of genes and the activity of signaling pathways such as PI3K/Akt, NF-κB, MAPK (ERK), JNK and TGF-β/Smad. Epigenetic modifications mediate the postponed effects of glucose fluctuations. The multiple deteriorative effects of GV provide further support for considering it as a therapeutic target in diabetes.

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“…Future analysis involving perturbation of these cell line-specific genes could provide further insight into the role of these genes in cell growth in vitro. Other studies have shown locus-specific DNA methylation changes associated with culture-specific conditions, such as length of time in culture, passage number [ 34 , 44 , 45 , 46 ], and altered levels of sera in media [ 47 , 48 , 49 ]. Similar to our analyses here, these studies generally showed global methylation patterns were maintained throughout long-term culture, but some significant differences were observed at specific CpG sites.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Global DNA Methylation Patterns in Human Melanoma Tissues and Their Derivative Cell Lines

Rodger

Almomani

Ludgate

et al. 2021

Cancers

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DNA methylation is a heritable epigenetic mark that is fundamental to mammalian development. Aberrant DNA methylation is an epigenetic hallmark of cancer cells. Cell lines are a critical in vitro model and very widely used to unravel mechanisms of cancer cell biology. However, limited data are available to assess whether DNA methylation patterns in tissues are retained when cell lines are established. Here, we provide the first genome-scale sequencing-based methylation map of metastatic melanoma tumour tissues and their derivative cell lines. We show that DNA methylation profiles are globally conserved in vitro compared to the tumour tissue of origin. However, we identify sites that are consistently hypermethylated in cell lines compared to their tumour tissue of origin. The genes associated with these common differentially methylated regions are involved in cell metabolism, cell cycle and apoptosis and are also strongly enriched for the H3K27me3 histone mark and PRC2 complex-related genes. Our data indicate that although global methylation patterns are similar between tissues and cell lines, there are site-specific epigenomic differences that could potentially impact gene expression. Our work provides a valuable resource for identifying false positives due to cell culture and for better interpretation of cancer epigenetics studies in the future.

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Glucose-induced, duration-dependent genome-wide DNA methylation changes in human endothelial cells

Cited by 13 publications

References 73 publications

The Long Non-Coding RNA HOTAIR Is a Critical Epigenetic Mediator of Angiogenesis in Diabetic Retinopathy

The Long Non-Coding RNA HOTAIR Is a Critical Epigenetic Mediator of Angiogenesis in Diabetic Retinopathy

Glucose Variability: How Does It Work?

Comparison of Global DNA Methylation Patterns in Human Melanoma Tissues and Their Derivative Cell Lines

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