RNA-sequencing analysis of high glucose-treated monocytes reveals novel transcriptome signatures and associated epigenetic profiles

Miao, Feng; Chen, Zhuo; Zhang, Lingxiao; Wang, Jinhui; Gao, Harry; Wu, Xiwei; Natarajan, Rama

doi:10.1152/physiolgenomics.00001.2013

Cited by 29 publications

(28 citation statements)

References 56 publications

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“…Hence, we focused our analysis on identifying key pathways, biological processes and networks subject to fetal sex influences with the aim to explain reported differences in placental function and disparity in pregnancy outcome. This approach of using genomic variation, even more modest that here, and sets of functionally related genes to analyze regulated pathways and networks is not novel [32], [33]. The pathways we have identified are the overlapping results of different software packages used for gene ontology analysis, making our findings robust.…”

Section: Discussionmentioning

confidence: 77%

The Human Placental Sexome Differs between Trophoblast Epithelium and Villous Vessel Endothelium

et al. 2013

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Molecular mechanisms underlying sexual dimorphism in mammals, fetal sex influences on intrauterine development, and the sex-biased susceptibility for selected diseases in adulthood are novel areas of current research. As importantly, two decades of multifaceted research has established that susceptibility to many adult disorders originates in utero, commonly secondary to the effects of placental dysfunction. We hypothesized that fetal sex influences gene expression and produces functional differences in human placentas. We thus extended previous studies on sexual dimorphism in mammals, which used RNA isolated from whole tissues, to investigate the effects of sex on four cell-phenotypes within a single key tissue, human placental villi. The cells studied included cytotrophoblasts, syncytiotrophoblast, arterial and venous endothelial cells. The cells were isolated from placentas of male or female fetuses and subjected to microarray analysis. We found that fetal sex differentially affected gene expression in a cell-phenotype dependent manner among all four cell-phenotypes. The markedly enriched pathways in males were identified to be signaling pathways for graft-versus-host disease as well as the immune and inflammatory systems that parallel the reported poorer outcome of male fetuses. Our study is the first to compare global gene expression by microarray analysis in purified, characterized, somatic cells from a single human tissue, i.e. placental villi. Importantly, our findings demonstrate that there are cell-phenotype specific, and tissue-specific, sex-biased responses in the human placenta, suggesting fetal sex should be considered as an independent variable in gene expression analysis of human placental villi.

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Section: Discussionmentioning

confidence: 77%

The Human Placental Sexome Differs between Trophoblast Epithelium and Villous Vessel Endothelium

et al. 2013

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“…TXNIP expression is highly induced by HG in various cell types (46)(47)(48), which by inhibiting thioredoxin, subsequently causes oxidative stress and apoptosis. Recently, TXNIP up-regulation in the diabetic kidney was reported to be associated with changes in certain histone PTMs (49).…”

Section: Resultsmentioning

confidence: 99%

Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

Chen

Miao

Paterson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We examined whether persistence of epigenetic DNA methylation (DNA-me) alterations at specific loci over two different time points in people with diabetes are associated with metabolic memory, the prolonged beneficial effects of intensive vs. conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term followup Epidemiology of Diabetes Interventions and Complications (EDIC) Study. We compared DNA-me profiles in genomic DNA of whole blood (WB) isolated at EDIC Study baseline from 32 cases (DCCT conventional therapy group subjects showing retinopathy or albuminuria progression by EDIC Study year 10) vs. 31 controls (DCCT intensive therapy group subjects without complication progression by EDIC year 10). DNA-me was also profiled in blood monocytes (Monos) of the same patients obtained during EDIC Study years 16-17. In WB, 153 loci depicted hypomethylation, and 225 depicted hypermethylation, whereas in Monos, 155 hypomethylated loci and 247 hypermethylated loci were found (fold change ≥1.3; P < 0.005; cases vs. controls). Twelve annotated differentially methylated loci were common in both WB and Monos, including thioredoxin-interacting protein (TXNIP), known to be associated with hyperglycemia and related complications. A set of differentially methylated loci depicted similar trends of associations with prior HbA1c in both WB and Monos. In vitro, high glucose induced similar persistent hypomethylation at TXNIP in cultured THP1 Monos. These results show that DNA-me differences during the DCCT persist at certain loci associated with glycemia for several years during the EDIC Study and support an epigenetic explanation for metabolic memory.T he landmark Diabetes Control and Complications Trial (DCCT; 1983-1993 clearly showed that intensive (INT) glycemic control profoundly reduces the development and progression of microvascular complications in type 1 diabetes (T1D). The DCCT participants were subsequently followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) Study (1994 to present), during which all subjects were advised to practice INT treatment. Surprisingly, those previously assigned to conventional (CONV) therapy continued to develop complications, such as nephropathy, retinopathy, and macrovascular diseases, at significantly higher rates than the previous INT therapy group, despite nearly similar HbA1c levels during the EDIC Study (1-3). This persistence of benefit from early application of INT therapy, called "metabolic memory," is an enigma in the field of T1D: recent studies have suggested the involvement of epigenetic mechanisms (4-9).Epigenetics is the study of mostly heritable changes in gene expression and phenotype that occur without alterations in the underlying DNA sequence. Epigenetic states are affected by environmental factors, such as aberrant nutrition and metabolic states (4, 6-8, 10). DNA methylation (DNA-me; the classic epigenetic mark) and posttranslational modifications (PTMs) of histo...

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“…Studies by Maio et al . identified genes differentially expressed in normal vs. high glucose in human THP-1 cells by RNA-seq [ 41 ], but did not report PRMT2 as a gene that was down regulated in high glucose. This could reflect differences in experimental design (acute high glucose stimulation in their study vs. chronic high glucose treatment in ours) or cell type (undifferentiated THP-1 monocytes vs. differentiated BMDMs).…”

Section: Discussionmentioning

confidence: 99%

LXR-Mediated ABCA1 Expression and Function Are Modulated by High Glucose and PRMT2

et al. 2015

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High cholesterol and diabetes are major risk factors for atherosclerosis. Regression of atherosclerosis is mediated in part by the Liver X Receptor (LXR) through the induction of genes involved in cholesterol transport and efflux. In the context of diabetes, regression of atherosclerosis is impaired. We proposed that changes in glucose levels modulate LXR-dependent gene expression. Using a mouse macrophage cell line (RAW 264.7) and primary bone marrow derived macrophages (BMDMs) cultured in normal or diabetes relevant high glucose conditions we found that high glucose inhibits the LXR-dependent expression of ATP-binding cassette transporter A1 (ABCA1), but not ABCG1. To probe for this mechanism, we surveyed the expression of a host of chromatin-modifying enzymes and found that Protein Arginine Methyltransferase 2 (PRMT2) was reduced in high compared to normal glucose conditions. Importantly, ABCA1 expression and ABCA1-mediated cholesterol efflux were reduced in Prmt2 -/- compared to wild type BMDMs. Monocytes from diabetic mice also showed decreased expression of Prmt2 compared to non-diabetic counterparts. Thus, PRMT2 represents a glucose-sensitive factor that plays a role in LXR-mediated ABCA1-dependent cholesterol efflux and lends insight to the presence of increased atherosclerosis in diabetic patients.

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RNA-sequencing analysis of high glucose-treated monocytes reveals novel transcriptome signatures and associated epigenetic profiles

Cited by 29 publications

References 56 publications

The Human Placental Sexome Differs between Trophoblast Epithelium and Villous Vessel Endothelium

The Human Placental Sexome Differs between Trophoblast Epithelium and Villous Vessel Endothelium

Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

LXR-Mediated ABCA1 Expression and Function Are Modulated by High Glucose and PRMT2

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