Dopachrome tautomerase is a retinoblastoma-specific gene, and its proximal promoter is preferentially active in human retinoblastoma cells.

Purpose: Retinoblastoma (RB) is a malignant childhood intraocular tumor. Current treatment options for RB have undesirable side effects. A comprehensive understanding of gene expression in human RB is essential for the development of safe and effective new therapies. Methods: We reviewed published microarray and RNA sequencing studies in which gene expression profiles were compared between human RB and normal retina tissues. We investigated the expression of genes of interest using quantitative reverse transcription PCR. We examined the activities of cloned promoter DNA fragments with luciferase assay. Results: Dopachrome tautomerase (DCT) was among the most overexpressed genes in RB in published studies. We found that DCT was highly expressed in six of 13 samples microdissected from Thai RB tissues. Expression of DCT was absent or barely detected in retina tissues, various human ocular cells, and major organs. We also demonstrated that the -657 to +411 DCT promoter fragment efficiently directs RB cell-specific transcription of the luciferase reporter gene in cell lines. Conclusions: The present work highlights that DCT is one of the most RB-specific genes. The regulatory elements required for this cell-specific gene expression are likely located within its proximal promoter.

14-weeks combined exercise epigenetically modulated 118 genes of menopausal women with prediabetes.

Background: Pre-diabetes precedes Diabetes Mellitus (DM) disease and is a critical period for hyperglycemia treatment, especially for menopausal women, considering all metabolic alterations due to hormonal changes. Recently, the literature has demonstrated the role of physical exercise in epigenetic reprogramming to modulate the gene expression patterns of metabolic conditions, such as hyperglycemia, and prevent DM development. In the present study, we hypothesized that physical exercise training could modify the epigenetic patterns of women with poor glycemic control. Methods: 48 post-menopause women aged 60.3 ± 4.5 years were divided according to their fasting blood glucose levels into two groups: Prediabetes Group, PG (n=24), and Normal Glucose Group, NGG (n=24). All participants performed 14 weeks of physical exercise three times a week. The Infinium Methylation EPIC BeadChip measured the participants' Different Methylated Regions (DMRs). Results: Before the intervention, the PG group had 12 DMRs compared to NGG. After the intervention, five DMRs remained different. Interestingly, when comparing the PG group before and after training, 118 DMRs were found. The enrichment analysis revealed that the genes were related to different biological functions such as energy metabolism, cell differentiation, and tumor suppression. Conclusion: Physical exercise is a relevant alternative in treating hyperglycemia and preventing DM in post-menopause women with poor glycemic control.

Psychosocial stress is associated with benign breast disease in young Chinese women: results from Project ELEFANT.

PURPOSE: Psychosocial stress, including bereavement and work-related stress, is associated with the risk of breast cancer. However, it is unknown whether it may also be linked with increased risk of benign breast disease (BBD). METHODS: Our study leveraged 61,907 women aged 17-55 years old from the Project ELEFANT study. BBD was diagnosed by clinician. Self-reported data on psychosocial stress over a 10-year period was retrospectively collected from questionnaires and categorised by cause (work, social and economic) and severity (none, low and high). Odd ratios (ORs) for the development of BBD were estimated using logistic regression. The model was adjusted for age, BMI, TSH levels, smoking, alcohol consumption, family history, age of menarche, oral contraceptive usage, education and occupation. RESULTS: Within our study, 8% (4,914) of participants were diagnosed with BBD. Work-related stress [OR 1.57, 95% confidence interval (CI) 1.46-1.69] and financial stress (OR 1.34, 95% CI 1.24-1.44) were significantly associated with BBD incidence, with a smaller but still significant association with social stress (OR 1.11, 95% CI 1.01-1.21). The associations remained significant after exclusion of participants with first- and second-degree family history of breast disease. The presence of multiple forms of stress did not synergistically increase risk. The neutrophil-lymphocyte ratio (NLR), a marker of systemic inflammation and prognostic marker for breast cancer, was not associated with BBD. CONCLUSIONS: Psychosocial stress, particularly work-related and financial stress, is associated with increased risk of benign breast disease among young Chinese women.

Dietary Intervention Modifies DNA Methylation Age Assessed by the Epigenetic Clock.

SCOPE: Alterations in DNA methylation patterns are correlated with aging, environmental exposures, and disease pathophysiology; the possibility of reverting or preventing these processes through dietary intervention is gaining momentum. In particular, methyl donors that provide S-adenosyl-methionine for one-carbon metabolism and polyphenols such as flavanols that inhibit the activity of DNA methyltransferases (DNMTs) can be key modifiers of epigenetic patterns. METHODS AND RESULTS: DNA methylation patterns are assessed in publicly available Illumina Infinium 450K methylation datasets from intervention studies with either folic acid + vitamin B12 (GSE74548) or monomeric and oligomeric flavanols (MOF) (GSE54690) in 44 and 13 participants, respectively. Global DNA methylation levels are increased in unmethylated regions such as CpG islands and shores following folic acid + vitamin B12 supplementation and decreased in highly methylated regions, including shelves and open-seas, following intervention with MOF. After supplementation with folic acid + vitamin B12, epigenetic age, estimated by the Horvath "epigenetic clock" model, is reduced in women with the MTHFR 677CC genotype. CONCLUSIONS: The effects of supplementation with folic acid + vitamin B12 and MOF on DNA methylation age are dependent upon gender and MTHFR genotype. Additionally, the findings demonstrate the potential for these dietary factors to modulate global DNA methylation profiles.

Genome-Wide Analysis of ChREBP Binding Sites on Male Mouse Liver and White Adipose Chromatin.

Glucose is an essential nutrient that directly regulates the expression of numerous genes in liver and adipose tissue. The carbohydrate response element-binding protein (ChREBP) links glucose as a signaling molecule to multiple glucose-dependent transcriptional regulatory pathways, particularly genes involved in glycolytic and lipogenic processes. In this study, we used chromatin immunoprecipitation followed by next-generation sequencing to identify specific ChREBP binding targets in liver and white adipose tissue. We found a large number of ChREBP binding sites, which are attributable to 5825 genes in the liver, 2418 genes in white adipose tissue, and 5919 genes in both tissues. The majority of these target genes were involved in known metabolic processes. Pathways in insulin signaling, the adherens junction, and cancers were among the top 5 pathways in both tissues. Motif analysis revealed a consensus sequence CAYGYGnnnnnCRCRTG that was commonly shared by ChREBP binding sites. Putative ChREBP binding sequences were enriched on promoters of genes involved in insulin signaling pathway, insulin resistance, and tumorigenesis.