Involvement Of Histone Acetylation Research Articles

P38 and ERK1/2-Dependent Activation of c-Jun Is Required for the Downregulation of Oxidative Stress-Induced ERα in Hypothalamic Astrocytes

Introduction: Gonadotropin-releasing hormone (GnRH) is a hypothalamic neuropeptide that plays important roles in the female fertility. Accumulating evidence suggests that ERα present in the astrocytes of the hypothalamus region is essential for production of GnRH. The astrocytes display age-related senescence associated to oxidative stress induced by the estrogen metabolites. However, it is still unclear whether and how ERα expression changes during astrocyte aging. Methods: Immunofluorescence was performed to analyze the ERα gene levels in hypothalamic astrocytes of naturally aging C57BL/6J female mice. We employed an oxidative stress cell model receiving 2-hydroxyestradiol (2OH-E2) intervention to confirm the downregulation of ERα expression in primary astrocytes. Western blot analysis was used to explore which oxidative stress signaling pathways induced loss of the ERα gene. Finally, ChIP-qPCR was employed to evaluate whether the c-Jun protein is able to regulate ERα gene expression. Results: Compared to young mice, we found that the ERα expression of mid-aged mice was significantly decreased. In hypothalamic astrocytes, 2OH-E2 treatment significantly reduced the expression of the ERα gene. Moreover, we observed that transcription factor c-Jun could directly inhibit transcriptional ERα gene expression and might also reduce it by decreasing H3K27 acetylation at promoter regions. Administration of the antioxidants Rg1 and astaxanthin significantly attenuated the decrease in ERα gene expression induced by oxidative stress. Conclusions: The current data demonstrate that oxidative stress leads to loss of ERα involving the activation of the p38 and ERK1/2 pathways and the induction of the c-Jun protein in hypothalamic astrocytes. C-Jun protein regulates ERα gene expression via direct transcriptional repression or involving histone acetylation modifications at ERα gene promoter sites.

The Inflammatory Effect of Epigenetic Factors and Modifications in Depressive Disorder: A Review.

Depressive disorder is one of the most common mental diseases and has become one of the three major causes of disability worldwide. Although some of the pathological mechanisms have been analyzed, the corresponding drug therapy has only achieved about 30% of curative effects. However, the pathological mechanism of depression is very complex, and the relationship between its complicated pathological mechanisms is still elusive. In recent years, more and more evidence shows that environmental stress induces stable changes in gene expression through the epigenetic mechanism which plays a vital role in the pathogenesis of the disease. Neuroinflammation is considered to be a key pathological mechanism of depression. The aim of the study was to explore the relationship between epigenetic mechanism and neuroinflammation in the pathological process of depression. In this paper, we review the crucial role of neuroinflammation in complex pathological mechanisms, especially its complex interrelationship with neurotransmitters, neuroendocrine, neurogenesis, and neuronal plasticity, which play a key role in the pathology of depression. The relationship between epigenetic mechanism and neuroinflammation in the pathological process of depression has been discussed, which mainly involves histone acetylation, histone methylation, DNA methylation, and non-coding RNA association. This review will help to understand the role of epigenetic mechanisms in depression and its related inflammatory responses and provide direction and guidance for future research.

MiR172 Regulates WUS during Somatic Embryogenesis in Arabidopsis via AP2.

In plants, the embryogenic transition of somatic cells requires the reprogramming of the cell transcriptome, which is under the control of genetic and epigenetic factors. Correspondingly, the extensive modulation of genes encoding transcription factors and miRNAs has been indicated as controlling the induction of somatic embryogenesis in Arabidopsis and other plants. Among the MIRNAs that have a differential expression during somatic embryogenesis, members of the MIRNA172 gene family have been identified, which implies a role of miR172 in controlling the embryogenic transition in Arabidopsis. In the present study, we found a disturbed expression of both MIRNA172 and candidate miR172-target genes, including AP2, TOE1, TOE2, TOE3, SMZ and SNZ, that negatively affected the embryogenic response of transgenic explants. Next, we examined the role of AP2 in the miR172-mediated mechanism that controls the embryogenic response. We found some evidence that by controlling AP2, miR172 might repress the WUS that has an important function in embryogenic induction. We showed that the mechanism of the miR172-AP2-controlled repression of WUS involves histone acetylation. We observed the upregulation of the WUS transcripts in an embryogenic culture that was overexpressing AP2 and treated with trichostatin A (TSA), which is an inhibitor of HDAC histone deacetylases. The increased expression of the WUS gene in the embryogenic culture of the hdac mutants further confirmed the role of histone acetylation in WUS control during somatic embryogenesis. A chromatin-immunoprecipitation analysis provided evidence about the contribution of HDA6/19-mediated histone deacetylation to AP2-controlled WUS repression during embryogenic induction. The upstream regulatory elements of the miR172-AP2-WUS pathway might involve the miR156-controlled SPL9/SPL10, which control the level of mature miR172 in an embryogenic culture.

Involvement of histone acetylation in tomato resistance to Ralstonia solanacearum

Bacterial wilt (BW) is the most devastating vascular disease in tomato (Solanum lycopersicum L.), which caused by Ralstonia solanacearum (R. solanacearum). Although several strategies have been proposed to control BW, the molecular mechanisms are largely unknown. Here, we identify two tomato cultivars JG-No3 and XN021, which showed susceptible and resistant to R. solanacearum, respectively. Most defense-related genes were up-regulated in resistant cultivar XN021, whereas down-regulated in susceptible cultivar JG-No3. The expression of some histone deacetylases (HDACs) was reduced in XN021 compared to JG-No3. Furthermore, the disease symptoms were decreased in JG-No3 using the HDACs inhibitor, TSA (Trichostatin A) treatment. Silencing of SlHDA6, SlHDT1, SlHDT2, SlSRT1 and SlSRT2 using VIGS caused reducing disease incidence in susceptible cultivar JG-No3. In addition, histone H3 and H4 acetylation levels of defense-related genes were increased in both cultivars under R. solanacearum infection, especially XN021. Collectively, our results demonstrate that histone acetylation mediating by HDACs plays important roles in BW resistance in tomato. This study provides a new insight into the mechanism of disease response in BW.

Regulation of hepatic genes related to lipid metabolism and antioxidant enzymes by sodium butyrate supplementation

BackgroundRapid influx of energy caused by fasting/refeeding repeatedly enhances fatty acid synthesis leading to triacylglycerol accumulation and production of reactive oxygen species (ROS), increasing the risk of non-alcoholic steatohepatitis (NASH). Previous studies have reported that the ingestion of butyrate is effective at preventing hepatic disorders, which are accompanied by fat accumulation and inflammation. The aim of this study is to reveal the mechanism of action of butyrate, and thus we investigated the effects of dietary butyrate on the expressions of antioxidant enzymes in the livers of rats during refeeding following fasting. MethodsThirty-seven male rats were divided into six groups (6–7 animals per group): non-fasting, fasting, refeeding with a high sucrose diet as control for 12 or 24 h, and refeeding with a high sucrose diet containing 5% sodium butyrate (NaB) for 12 or 24 h. All groups except the non-fasting group were fasted for 72 h before refeeding. Statistical analysis was conducted among 4 refeeding groups (refeeding with the control diet for 12 or 24 h, and refeeding with a diet containing NaB for 12 or 24 h). ResultsSupplementation with NaB significantly reduced (p < 0.05) fatty acid synthase (Fas) gene expression and increased the expression of the carnitine palmitoyltransferase 1α (Cpt1a) gene, resulting in reduced triacylglycerol content in the livers of rats refed the NaB diet compared with controls at 24 h after the start of refeeding. The mRNA levels of the genes related to glutathione synthesis were significantly higher (p < 0.05) in the livers of the butyrate group than the control group. In addition, the mRNA level of Foxo3a, a transcription factor that regulates the expressions of antioxidant enzymes, was higher in the butyrate group than controls. The acetylation levels of histone H4 around the Foxo3a gene tended to be increased (p = 0.055) by refeeding with the NaB diet. ConclusionNaB supplementation in the diet for refeeding reduced the rate of lipid synthesis and stimulated fatty acid oxidation in the liver, which inhibited fat accumulation and the risk of NASH. The transcriptional regulation of Foxo3a involves histone acetylation around the gene.

Homeostasis of histone acetylation is critical for auxin signaling and root morphogenesis

The auxin signaling and root morphogenesis are harmoniously controlled by two counteracted teams including (1) auxin/indole-3-acetic acid (AUX/IAA)-histone deacetylase (HDA) and (2) auxin response factor (ARF)-histone acetyltransferase (HAT). The involvement of histone acetylation in the regulation of transcription was firstly reported a few decades ago. In planta, auxin is the first hormone group that was discovered and it is also the most studied phytohormone. Current studies have elucidated the functions of histone acetylation in the modulation of auxin signaling as well as in the regulation of root morphogenesis under both normal and stress conditions. Based on the recent outcomes, this review is to provide a hierarchical view about the functions of histone acetylation in auxin signaling and root morphogenesis. In this report, we suggest that the auxin signaling must be controlled harmoniously by two counteracted teams including (1) auxin/indole-3-acetic acid (AUX/IAA)-histone deacetylase (HDA) and (2) auxin response factor (ARF)-histone acetyltransferase (HAT). Moreover, the balance in auxin signaling is very critical to contribute to normal root morphogenesis.

Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma.

Core regulatory transcription factors (CR TFs) orchestrate the placement of super-enhancers (SEs) to activate transcription of cell-identity specifying gene networks, and are critical in promoting cancer. Here, we define the core regulatory circuitry of rhabdomyosarcoma (RMS) and identify critical CR TF dependencies. These CR TFs build SEs that have the largest levels of histone acetylation, yet paradoxically SEs also harbor the highest amounts of histone deacetylases (HDACs). We find that hyperacetylation selectively halts CR TF transcription. To investigate the architectural determinants of this phenotype, we developed Absolute Quantification of Architecture (AQuA) HiChIP, revealing erosion of native SE contacts, and aberrant spreading of contacts involving histone acetylation. Hyperacetylation removes RNA Pol2 from core regulatory genetic elements, and eliminates RNA-Pol2 but not BRD4 phase condensates. This study identifies a SE-specific requirement for balancing histone modification states to maintain SE architecture and CR TF transcription.

Brain STAT5 Modulates Long-Term Metabolic and Epigenetic Changes Induced by Pregnancy and Lactation in Female Mice.

Several metabolic and behavioral adaptations that emerge during pregnancy remain present after weaning. Thus, reproductive experience causes long-lasting metabolic programming, particularly in the brain. However, the isolate effects of pregnancy or lactation and the molecular mechanisms involved in these long-term modifications are currently unknown. In the current study, we investigated the role of brain signal transducer and activator of transcription-5 (STAT5), a key transcription factor recruited by hormones highly secreted during gestation or lactation, for the long-term adaptations induced by reproductive experience. In control mice, pregnancy followed by lactation led to increased body adiposity and reduced ambulatory activity later in life. Additionally, pregnancy+lactation induced long-term epigenetic modifications in the brain: we observed upregulation in hypothalamic expression of histone deacetylases and reduced numbers of neurons with histone H3 acetylation in the paraventricular, arcuate, and ventromedial nuclei. Remarkably, brain-specific STAT5 ablation prevented all metabolic and epigenetic changes observed in reproductively experienced control female mice. Nonetheless, brain-specific STAT5 knockout (KO) mice that had the experience of pregnancy but did not lactate showed increased body weight and reduced energy expenditure later in life, whereas pregnancy KO and pregnancy+lactation KO mice exhibited improved insulin sensitivity compared with virgin KO mice. In summary, lactation is necessary for the long-lasting metabolic effects observed in reproductively experienced female mice. In addition, epigenetic mechanisms involving histone acetylation in neuronal populations related to energy balance regulation are possibly associated with these long-term consequences. Finally, our findings highlighted the key role played by brain STAT5 signaling for the chronic metabolic and epigenetic changes induced by pregnancy and lactation.

A novel epigenetic mechanism of FXR inhibiting GLP-1 secretion via miR-33 and its downstream targets

Type II diabetes is a complex, chronic, and progressive disease. Previously, we demonstrate that FXR inhibits GLP-1 secretion via interacting with CREB to inhibit the transcriptional activity of CREB, thus promoting the development of type II diabetes. Epigenetic modifications, such as DNA methylation, histone acetylation, and post-transcriptional RNA regulation, are essential mediators contributing to diabetes-associated morbidity and mortality. Thus, we attempted to investigate the epigenetic mechanisms of FXR modulating GLP-1 secretion. Firstly, the involvement of histone acetylation, DNA methylation, and post-transcriptional regulation in FXR inhibiting GLP-1 secretion was verified. As FXR overexpression significantly inhibited the activity of GCG 3′-UTR, we hypothesize that miRNA might participate in the mechanism. Two online tools and real-time PCR revealed that FXR promoted miR-33 expression. Moreover, miR-33 inhibited the expression of GCG and CREB1 through direct targeting in STC-1 cells. FXR overexpression in STC-1 cells significantly reduced the mRNA expression and protein levels of both GCG and CREB1, as well as the secretion of GLP-1; miR-33 inhibition exerted opposing effects. More importantly, the effects of FXR overexpression were significantly reversed by miR-33 inhibition, indicating that FXR inhibited GLP-1 secretion through promoting miR-33 expression, therefore inhibiting the expression of miR-33 targets, GCG and CREB1. In conclusion, we provide a novel epigenetic mechanism by which FXR inhibits the secretion of GLP-1 through miR-33 and its two downstream targets, GCG and CREB1. These findings might provide innovative strategies for improving type II diabetes, which needs further in vivo and clinical investigation.

EFFECT OF LUNASIN-ENRICHED SOY EXTRACT ON HISTONE DEACETYLASE EXPRESSION IN DISTAL COLON EPITHELIAL CELLS FROM AOM/DSS-INDUCED MICE

Objective: Lunasin peptide, with its chemopreventive and chemotherapeutic abilities, is known to affect carcinogenesis via epigenetic regulation involving histone acetylation. This study investigated lunasin, which can be found in soy, and its effects towards histone deacetylase (HDAC] expression in a mouse model of carcinogenesis.&#x0D; Methods: Thirty Swiss Webster mice were grouped into normal, positive control, negative control, and experimental groups. Except for the normal group, mice underwent carcinogenesis induction through azoxymethane (AOM] and dextran sodium sulfate (DSS] injection. Experimental mice received lunasin-enriched soy extract at a dosage of 250 mg/kg BW (kilogram body weight), 300 mg/kg BW, and 350 mg/kg BW for 4 w. Distal colon samples were stained by using immunohistochemistry (IHC]. HDAC expression was measured by IHC optical density score.&#x0D; Results: Average HDAC expression was 202.4% in the normal group, 239.3% in the negative control, 175.25% in the positive control, 202.03% at 250 mg/kg BW dose, 219.53% at 300 mg/kg, and 166.68% at 350 mg/kg BW. There was no significant difference between HDAC expression at 250 mg/kg BW and 300 mg/kg BW soy extract. However, at 350 mg/kg BW soy extract there were significant changes in HDAC expression.&#x0D; Conclusion: lunasin in soy extract at a 350 mg/kg BW dose can decrease HDAC expression in a colorectal cancer carcinogenesis model.

P-88 - Involvement of histone acetylation and methylation in SOD3 regulation in human monocytic THP-1 cells

Superoxide dismutase 3 (SOD3), a secretory SOD isozyme, displays a unique and cell-specific expression pattern, and epigenetics plays a critical role in its expression. To date, we have determined that histone acetylation governs phorbol ester (TPA)-elicited SOD3 expression in human monocytic THP-1 cells; however, the molecular mechanisms involving its induction remains unclear. Present data demonstrated that histone deacetylase 1 (HDAC1) and histone acetyltransferase (p300) coordinated SOD3 induction. Moreover, it was determined that myocyte enhancer factor 2 A (MEF2A) and MEF2D function as scaffold proteins, indicating that MEF2/HDAC1 or MEF2/p300 complex regulates SOD3 expression. On the other hand, asymmetric H4R3me2 (H4R3me2a), an epigenetic marker for transcription activation, was also induced in TPA-treated THP-1 cells, suggesting that histone methylation regulates SOD3 expression as well. As expected, our ChIP data clearly showed that the level of H4R3me2a within the proximal SOD3 promoter region was significantly enhanced. Overall, we have found that histone modifications including acetylation and methylation govern SOD3 expression in THP-1 cells.

Possible involvement of histone acetylation in the resistance and adaptation to stress in mice

Possible involvement of histone acetylation in the resistance and adaptation to stress in mice

Involvement of histone acetylation and deacetylation in regulating auxin responses and associated phenotypic changes in plants

The most recent outcomes about the transcription factors and transcription complexes mediated auxin signaling pathway by the histone acetylation and deacetylation. The phytohormone auxin, is required to regulate its accumulation spatiotemporally and responses to orchestrate various developmental levels in plants. Histone acetylation and deacetylation modulate auxin biosynthesis, its distribution and accumulation. In the absence of auxin, histone deacetylase represses the expression of auxin-responsive genes. Various transcription factors and transcription complexes facilitate the proper regulation of auxin signaling pathway genes. The primary and lateral root development, promotion of flowering and initiation of seed germination are all regulated by auxin-mediated histone acetylation and deacetylation. These findings conclude the auxin mode ofaction, which is mediated by histone acetylation and deacetylation, and associated phenotypic responses in plants, along with the underlying mechanism of these modifications.

Epigenetic induction of melatonin MT1 receptors by valproate: Neurotherapeutic implications

We have reported that the anticonvulsant/mood stabilizer and histone deacetylase (HDAC) inhibitor valproate (VPA) induces expression of melatonin receptors both in vitro and in vivo, but the mechanisms involved were not known. Here we show that pharmacological inhibition of CREB, PKC, PI3K, or GSK3β signaling pathways, which are known targets for VPA, do not prevent its upregulation of melatonin MT1 receptors in rat C6 glioma cells. M344, an HDAC inhibitor unrelated to VPA, mimics the effects of VPA on MT1 expression, whereas valpromide, a VPA derivative lacking HDAC inhibitory activity, does not. Furthermore, VPA, at a concentration which upregulates the MT1 receptor, induces histone H3 hyperacetylation along the length of the MT1 receptor promoter. These results show that an epigenetic mechanism involving histone acetylation underlies induction of MT1 receptor expression by VPA. Given the neuropsychiatric effects of melatonin coupled with evidence that VPA upregulates melatonin receptors in the rat brain, these findings suggest that the melatonergic system contributes to the psychotropic effects of VPA.

Rice Homeodomain Protein WOX11 Recruits a Histone Acetyltransferase Complex to Establish Programs of Cell Proliferation of Crown Root Meristem.

Shoot-borne crown roots are the major root system in cereals. Previous work has shown that the Wuschel-related homeobox gene WOX11 is necessary and sufficient to promote rice (Oryza sativa) crown root emergence and elongation. Here, we show that WOX11 recruits the ADA2-GCN5 histone acetyltransferase module to activate downstream target genes in crown root meristem. Rice ADA2 and GCN5 genes are highly expressed in root meristem and are shown to be essential for cell division and growth. WOX11 and ADA2-GCN5 commonly target and regulate a set of root-specific genes involved in energy metabolism, cell wall biosynthesis, and hormone response, some of which are known to be important for root development. The results indicate that the recruitment of ADA2-GCN5 by WOX11 establishes gene expression programs of crown root meristem cell division and suggest that permissive chromatin modification involving histone acetylation is a strategy for WOX11 to stimulate root meristem development.

Sas3 and Ada2(Gcn5)-dependent histone H3 acetylation is required for transcription elongation at the de-repressed FLO1 gene.

The Saccharomyces cerevisiae FLO1 gene encodes a cell wall protein that imparts cell–cell adhesion. FLO1 transcription is regulated via the antagonistic activities of the Tup1–Cyc8 co-repressor and Swi–Snf co-activator complexes. Tup1–Cyc8 represses transcription through the organization of strongly positioned, hypoacetylated nucleosomes across gene promoters. Swi–Snf catalyzes remodeling of these nucleosomes in a mechanism involving histone acetylation that is poorly understood. Here, we show that FLO1 de-repression is accompanied by Swi–Snf recruitment, promoter histone eviction and Sas3 and Ada2(Gcn5)-dependent histone H3K14 acetylation. In the absence of H3K14 acetylation, Swi–Snf recruitment and histone eviction proceed, but transcription is reduced, suggesting these processes, while essential, are not sufficient for de-repression. Further analysis in the absence of H3K14 acetylation reveals RNAP II recruitment at the FLO1 promoter still occurs, but RNAP II is absent from the gene-coding region, demonstrating Sas3 and Ada2-dependent histone H3 acetylation is required for transcription elongation. Analysis of the transcription kinetics at other genes reveals shared mechanisms coupled to a distinct role for histone H3 acetylation, essential at FLO1, downstream of initiation. We propose histone H3 acetylation in the coding region provides rate-limiting control during the transition from initiation to elongation which dictates whether the gene is permissive for transcription.

Thyroid Hormone-Dependent Epigenetic Regulation of Melanocortin 4 Receptor Levels in Female Offspring of Obese Rats.

Maternal obesity is a risk factor for offspring obesity. The melanocortin 4 receptor (Mc4r) is one of the mediators of food intake and energy balance. The present study examined the epigenetic mechanisms underlying altered Mc4r levels in the hypothalamic paraventricular nucleus in the offspring of high-fat diet (HFD)-induced obese dams and sought to elucidate the role of thyroid hormones in epigenetic regulation and tagging of their nucleosome at the Mc4r promoter. Female Wistar rats were fed an HFD or standard chow from weaning through gestation and lactation. Epigenetic alterations were analyzed in the offspring on postnatal day 21 at the Mc4r promoter using chromatin immunoprecipitation and bisulfite sequencing. To study the role of triiodothyronine (T3) in Mc4r downregulation, dams received methimazole (MMI), an inhibitor of thyroid hormone production. Offspring of HFD-fed dams had a greater body weight, elevated plasma T3 concentrations, and lower Mc4r messenger RNA levels than controls. At the Mc4r promoter, offspring of HFD-fed mothers demonstrated increased histone 3 lysine 27 acetylation (H3K27ac) with a greater association to thyroid hormone receptor-β (TRβ), an inhibitor of Mc4r transcription. Moreover, TRβ coimmunoprecipitated with H3K27ac, supporting their presence in the same complex. Maternal MMI administration prevented the HFD reduction in Mc4r levels, the increase in TRβ, and the increase in the TRβ-H3K27ac association, providing further support for the role of T3 in downregulating Mc4r levels. These findings demonstrate that a perinatal HFD environment affects Mc4r regulation through a T3 metabolic pathway involving histone acetylation of its promoter.

Histone Acetylation and the Regulation of Major Histocompatibility Class II Gene Expression.

Major histocompatibility complex (MHC) class II molecules are essential for processing and presenting exogenous pathogen antigens to activate CD4+ T cells. Given their central role in adaptive immune responses, MHC class II genes are tightly regulated in a tissue- and activation-specific manner. The regulation of MHC class II gene expression involves various transcription factors that interact with conserved proximal cis-acting regulatory promoter elements, as well as MHC class II transactivator that interacts with a variety of chromatin remodeling machineries. Recent studies also identified distal regulatory elements within MHC class II gene locus that provide enormous insight into the long-range coordination of MHC class II gene expression. Novel therapeutic modalities that can modify MHC class II genes at the epigenetic level are emerging and are currently in preclinical and clinical trials. This review will focus on the role of chromatin remodeling, particularly remodeling that involves histone acetylation, in the constitutive and inducible regulation of MHC class II gene expression.

Epigenetic regulation of the thioredoxin-interacting protein (TXNIP) gene by hyperglycemia in kidney

Diabetic kidney disease is the leading cause of end-stage renal disease. Genetic factors have been suggested to contribute to its susceptibility. However, results from genetic studies are disappointing possibly because the role of glucose in diabetic kidney disease predisposed by epigenetic mechanisms has not been taken into account. Since thioredoxin-interacting protein (TXNIP) has been shown to play an important role in the pathogenesis of diabetic kidney disease, we tested whether glucose could induce expression of TXNIP in the kidney by epigenetic mechanisms. In kidneys from diabetic Sur1-E1506K(+/+) mice, hyperglycemia-induced Txnip expression was associated with stimulation of activating histone marks H3K9ac, H3K4me3, and H3K4me1, as well as decrease in the repressive histone mark H3K27me3 at the promoter region of the gene. Glucose also coordinated changes in histone marks and TXNIP gene expression in mouse SV40 MES13 mesangial cells and the normal human mesangial cell line NHMC. The involvement of histone acetylation in glucose-stimulated TXNIP expression was confirmed by reversing or enhancing acetylation using the histone acetyltransferase p300 inhibitor C646 or the histone deacetylase inhibitor trichostatin A. Thus, glucose is a potent inducer of histone modifications, which could drive expression of proinflammatory genes and thereby predispose to diabetic kidney disease.

Genetic and epigenetic modifications in the pathogenesis of diabetic retinopathy: a molecular link to regulate gene expression.

Intensification in the frequency of diabetes and the associated vascular complications has been a root cause of blindness and visual impairment worldwide. One such vascular complication which has been the prominent cause of blindness; retinal vasculature, neuronal and glial abnormalities is diabetic retinopathy (DR), a chronic complicated outcome of Type 1 and Type 2 diabetes. It has also become clear that "genetic" variations in population alone can't explain the development and progression of diabetes and its complications including DR. DR experiences engagement of foremost mediators of diabetes such as hyperglycemia, oxidant stress, and inflammatory factors that lead to the dysregulation of "epigenetic" mechanisms involving histone acetylation and histone and DNA methylation, chromatin remodeling and expression of a complex set of stress-regulated and disease-associated genes. In addition, both elevated glucose concentration and insulin resistance leave a robust effect on epigenetic reprogramming of the endothelial cells too, since endothelium associated with the eye aids in maintaining the vascular homeostasis. Furthermore, several studies conducted on the disease suggest that the modifications of the epigenome might be the fundamental mechanism(s) for the proposed metabolic memory' resulting into prolonged gene expression for inflammation and cellular dysfunction even after attaining the glycemic control in diabetics. Henceforth, the present review focuses on the aspects of genetic and epigenetic alterations in genes such as vascular endothelial growth factor and aldose reductase considered being associated with DR. In addition, we discuss briefly the role of the thioredoxin-interacting protein TXNIP, which is strongly induced by high glucose and diabetes, in cellular oxidative stress and mitochondrial dysfunction potentially leading to chromatin remodeling and ocular complications of diabetes. The identification of disease-associated genes and their epigenetic regulations will lead to potential new drugs and gene therapies as well as personalized medicine to prevent or slow down the progression of DR.