Induction of the TEAD Coactivator VGLL1 by Estrogen Receptor-Targeted Therapy Drives Resistance in Breast Cancer.

Resistance to endocrine therapies (ET) is common in estrogen receptor (ER)-positive breast cancer, and most relapsed patients die with ET-resistant disease. Although genetic mutations provide explanations for some relapses, mechanisms of resistance remain undefined in many cases. Drug-induced epigenetic reprogramming has been shown to provide possible routes to resistance.

Induction of APOBEC3B expression by chemotherapy drugs is mediated by DNA-PK-directed activation of NF-κB.

The mutagenic APOBEC3B (A3B) cytosine deaminase is frequently over-expressed in cancer and promotes tumour heterogeneity and therapy resistance. Hence, understanding the mechanisms that underlie A3B over-expression is important, especially for developing therapeutic approaches to reducing A3B levels, and consequently limiting cancer mutagenesis. We previously demonstrated that A3B is repressed by p53 and p53 mutation increases A3B expression.

Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments.

Numerous anti-cancer drugs perturb thymidylate biosynthesis and lead to genomic uracil incorporation contributing to their antiproliferative effect. Still, it is not yet characterized if uracil incorporations have any positional preference. Here, we aimed to uncover genome-wide alterations in uracil pattern upon drug treatments in human cancer cell line models derived from HCT116.

Chromatin accessibility dynamics across development and ageing.

An essential step for understanding the transcriptional circuits that control development and physiology is the global identification and characterization of regulatory elements. Here, we present the first map of regulatory elements across the development and ageing of an animal, identifying 42,245 elements accessible in at least one stage. Based on nuclear transcription profiles, we define 15,714 protein-coding promoters and 19,231 putative enhancers, and find that both types of element can drive orientation-independent transcription.

p53 controls expression of the DNA deaminase APOBEC3B to limit its potential mutagenic activity in cancer cells.

Cancer genome sequencing has implicated the cytosine deaminase activity of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) genes as an important source of mutations in diverse cancers, with APOBEC3B (A3B) expression especially correlated with such cancer mutations. To better understand the processes directing A3B over-expression in cancer, and possible therapeutic avenues for targeting A3B, we have investigated the regulation of A3B gene expression. Here, we show that A3B expression is inversely related to p53 status in different cancer types and demonstrate that this is due to a direct and pivotal role for p53 in repressing A3B expression.

Expression of CDK7, Cyclin H, and MAT1 Is Elevated in Breast Cancer and Is Prognostic in Estrogen Receptor-Positive Breast Cancer.

Purpose: CDK-activating kinase (CAK) is required for the regulation of the cell cycle and is a trimeric complex consisting of cyclin-dependent kinase 7 (CDK7), Cyclin H, and the accessory protein, MAT1. CDK7 also plays a critical role in regulating transcription, primarily by phosphorylating RNA polymerase II, as well as transcription factors such as estrogen receptor-α (ER). Deregulation of cell cycle and transcriptional control are general features of tumor cells, highlighting the potential for the use of CDK7 inhibitors as novel cancer therapeutics.

Early-life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice.

A suboptimal early-life environment, due to poor nutrition or stress during pregnancy, can influence lifelong phenotypes in the progeny. Epigenetic factors are thought to be key mediators of these effects. We show that protein restriction in mice from conception until weaning induces a linear correlation between growth restriction and DNA methylation at ribosomal DNA (rDNA).

Sexually dimorphic gene expression emerges with embryonic genome activation and is dynamic throughout development.

Background: As sex determines mammalian development, understanding the nature and developmental dynamics of the sexually dimorphic transcriptome is important. To explore this, we generated 76 genome-wide RNA-seq profiles from mouse eight-cell embryos, late gestation and adult livers, together with 4 ground-state pluripotent embryonic (ES) cell lines from which we generated both RNA-seq and multiple ChIP-seq profiles. We complemented this with previously published data to yield 5 snap-shots of pre-implantation development, late-gestation placenta and somatic tissue and multiple adult tissues for integrative analysis.

Inactive or moderately active human promoters are enriched for inter-individual epialleles.

Background: Inter-individual epigenetic variation, due to genetic, environmental or random influences, is observed in many eukaryotic species. In mammals, however, the molecular nature of epiallelic variation has been poorly defined, partly due to the restricted focus on DNA methylation. Here we report the first genome-scale investigation of mammalian epialleles that integrates genomic, methylomic, transcriptomic and histone state information.

Buccals are likely to be a more informative surrogate tissue than blood for epigenome-wide association studies.

There is increasing evidence that interindividual epigenetic variation is an etiological factor in common human diseases. Such epigenetic variation could be genetic or non-genetic in origin, and epigenome-wide association studies (EWASs) are underway for a wide variety of diseases/phenotypes. However, performing an EWAS is associated with a range of issues not typically encountered in genome-wide association studies (GWASs), such as the tissue to be analyzed.

Guthrie card methylomics identifies temporally stable epialleles that are present at birth in humans.

A major concern in common disease epigenomics is distinguishing causal from consequential epigenetic variation. One means of addressing this issue is to identify the temporal origins of epigenetic variants via longitudinal analyses. However, prospective birth-cohort studies are expensive and time consuming.

Mitochondrial DNA copy number is modulated by genetic variation in the signal transducer and activator of transcription 3 (STAT3).

The regulation of mitochondrial DNA (mtDNA) copy number not only is critical for the maintenance of the normal mitochondrial function but has a strong clinical significance. A recent report revealed that the signal transducer and activator of transcription 3 (STAT3) is involved in the regulation of the mitochondrial function and is required for the optimal function of the electron transport chain. In this study, we explored whether gene variants in the STAT3 influence the leukocyte mtDNA copy number.

Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter.

Unlabelled: Insulin resistance (IR) and mitochondrial dysfunction play a central role in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). We hypothesized that genetic factors and epigenetic modifications occurring in the liver contribute to the IR phenotype. We specifically examined whether fatty liver and IR are modified by hepatic DNA methylation of the peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A) and mitochondrial transcription factor A (TFAM) promoters, and also evaluated whether liver mitochondrial DNA (mtDNA) content is associated with NAFLD and IR.

Methylation of TFAM gene promoter in peripheral white blood cells is associated with insulin resistance in adolescents.

Purpose: To explore whether DNA methylation of the mitochondrial transcription factor A (TFAM) promoter is associated with insulin resistance in a sample of adolescents with features of metabolic syndrome.

Methods: The data and blood samples were collected from 122 adolescents out of a cross-sectional study of 934 high-school students. The population was divided into two groups: noninsulin resistance (NIR) and insulin resistance (IR).

Role of genetic variation in insulin-like growth factor 1 receptor on insulin resistance and arterial hypertension.

Objective: To perform a two-stage study to explore the role of gene variants in the risk of insulin resistance and arterial hypertension.

Methods And Results: The selection of variants was performed by a first stage of in-silico analysis of the original genome-wide association data sets on genes involved in metabolic syndrome components, granted by the Diabetes Genetics Initiative and the Wellcome Trust Case-Control Consortium. We started by identifying single-nucleotide polymorphisms with a cutoff for association (P < 0.

Increased levels of resistin in rotating shift workers: a potential mediator of cardiovascular risk associated with circadian misalignment.

Objective: Shift work schedule has been associated with several health problems, including deleterious effects on the cardiovascular system. The present study aimed to evaluate the circulating levels of four biomarkers of atherosclerosis (soluble CD40 ligand [sCD40L], monocyte chemoattractant protein-1 [MCP-1], resistin, and plasminogen activator inhibitor-1 [PAI-1]) in a population-based sample of young adult men exposed to rotating shift work schedule in comparison with day workers.

Design And Participants: A total of 439 men aged 34.

Influence of hepatocyte nuclear factor 4alpha (HNF4alpha) gene variants on the risk of type 2 diabetes: a meta-analysis in 49,577 individuals.

Background: The nuclear receptor hepatocyte nuclear factor 4alpha (HNF4alpha) contributes to the regulation of a large fraction of liver and pancreatic islet transcriptomes.

Aim: To evaluate the influence of HNF4alpha polymorphisms across the entire locus on the occurrence of type 2 diabetes (T2D) by means of a meta-analysis.

Methods: We evaluated haplotype block structure of HNF4alpha variants owing to linkage disequilibrium (LD).

Maternal pregestational BMI is associated with methylation of the PPARGC1A promoter in newborns.

We explored peroxisome proliferator-activated receptor-gamma co-activator 1alpha gene (PPARGC1A), peroxisome proliferator-activated receptor-gamma gene (PPARG), and transcription factor A mitochondrial gene (Tfam) promoter DNA methylation in newborns between both extremes of abnormal fetal growth: Small (SGA) and large for gestational age (LGA) in relation to the mother's characteristics. We further sought for the association of rs9930506 variant at FTO gene and the promoter patterns of DNA methylation in the aforementioned genes, in relation to the offspring's birth weight. In a cross-sectional study, 88 healthy pregnant women and their babies were included.

Polymorphisms of MRP2 (ABCC2) are associated with susceptibility to nonalcoholic fatty liver disease.

Aims: We hypothesized that ABCC2 gene variants may contribute to susceptibility to nonalcoholic fatty liver disease (NAFLD). Additionally, we tested the hypothesis of a relation between gene variants and disease severity.

Patients And Methods: The study involved 167 individuals: 109 consecutively presenting unrelated patients with features of NAFLD and different stages of disease severity, and a group of 58 healthy individuals.

Genetic variants in STAT3 are associated with nonalcoholic fatty liver disease.

Aims: To investigate the role of gene variants and derived haplotypes of the STAT3 transcription factor in nonalcoholic fatty liver disease (NAFLD) and their relation with the clinical disease severity.

Patients And Methods: 108 patients with NAFLD and different stages of clinical disease severity, and a group of 55 healthy individuals were included in a Hospital-based study. We selected 3 tagSNPs showing a minor allele frequency >10% (rs2293152 C/G, rs6503695 C/T, and rs9891119 A/C) encompassing 68.

Genetic variants of Clock transcription factor are associated with individual susceptibility to obesity.

Background: Altering circadian rhythmicity results in pathophysiologic changes resembling metabolic syndrome and fat accumulation.

Objective: We investigated the role of gene variants and derived haplotypes of the CLOCK transcription factor in obesity and related quantitative metabolic traits.

Design: Lean (n = 715) and overweight or obese (n = 391) unrelated subjects aged 34.

Study of genetic variation in the STAT3 on obesity and insulin resistance in male adults.

Signal transducer and activator of transcription 3 (STAT3) plays an important role in hepatic glucose homeostasis and carbohydrate metabolism and has been implicated in the leptin-mediated energy homeostasis. We explored whether STAT3 gene variants are associated with obesity and insulin resistance in a well-characterized sample of 984 adult men (aged 34.4+/-8.

A decreased mitochondrial DNA content is related to insulin resistance in adolescents.

The aim of this study was to investigate whether mitochondrial DNA (mtDNA) content is associated with insulin resistance (IR) in a sample of adolescents with features of metabolic syndrome. We further studied the link between polymorphisms in three genes involved in mitochondrial biogenesis and the presence of deleted mtDNA and mtDNA content. Data and blood samples were collected from 175 adolescents out of a cross-sectional, population-based study of 934 high school students.