Long noncoding RNA PVT1 promotes cervical cancer progression through epigenetically silencing miR‐200b

Long noncoding RNA PVT1 has been reported to be dysregulated and play vital roles in a variety of cancers. However, the functions and molecular mechanisms of PVT1 in cervical cancer remain unclear. The objective of this study was to investigate the expression, clinical significance, biological roles, and underlying functional mechanisms of PVT1 in cervical cancer. Our results revealed that PVT1 is upregulated in cervical cancer tissues. Enhanced expression of PVT1 is associated with larger tumor size, advanced International Federation of Gynecology and Obstetrics stage, and poor prognosis of cervical cancer patients. Using gain‐of‐function and loss‐of‐function approaches, we demonstrated that overexpression of PVT1 promotes cervical cancer cells proliferation, cell cycle progression and migration, and depletion of PVT1 inhibits cervical cancer cell proliferation, cell cycle progression, and migration. Mechanistically, we verified that PVT1 binds to EZH2, recruits EZH2 to the miR‐200b promoter, increases histone H3K27 trimethylation level on the miR‐200b promoter, and inhibits miR‐200b expression. Furthermore, the effects of PVT1 on cervical cell proliferation and migration depend upon silencing of miR‐200b. Taken together, our findings confirmed that PVT1 functions as an oncogene in cervical cancer and indicated that PVT1 is not only an important prognostic marker, but also a potential therapy target for cervical cancer.     

The role of genetics and epigenetics in the pathogenesis of gestational diabetes mellitus

Diabetes mellitus (DM) is a heterogeneous group of disorders whose common trait is chronic hyperglycemia. Gestational diabetes mellitus (GDM) is one of the subtypes of DM that manifests during pregnancy. It is believed that 2%–5% of pregnancies worldwide are complicated with GDM, with the prevalence having significantly increased over the last decade. While the pathogenesis of the disease remains largely unknown, GDM is believed to be a result of interactions between genetic, epigenetic, and environmental factors. Linkage and association studies, including those that are genome-wide, have allowed us to identify complex genetic and epigenetic mechanisms that lead to the development of GDM. Multiple common variants in candidate genes such as potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11), glucokinase (GCK), or hepatocyte nuclear factor 1α (HNF1A) have been found to increase the disease risk. In this review, we provide a detailed overview of the current knowledge concerning the influence of genetics and epigenetics on the development of GDM.     

CTCF-dependent enhancer-blocking by alternative chromatin loop formation

The mechanism underlying enhancer-blocking by insulators is unclear. We explored the activity of human β-globin HS5, the orthologue of the CTCF-dependent chicken HS4 insulator. An extra copy of HS5 placed between the β-globin locus control region (LCR) and downstream genes on a transgene fulfills the classic predictions for an enhancer-blocker. Ectopic HS5 does not perturb the LCR but blocks gene activation by interfering with RNA pol II, activator and coactivator recruitment, and epigenetic modification at the downstream β-globin gene. Underlying these effects, ectopic HS5 disrupts chromatin loop formation between β-globin and the LCR, and instead forms a new loop with endogenous HS5 that topologically isolates the LCR. Both enhancer-blocking and insulator-loop formation depend on an intact CTCF site in ectopic HS5 and are sensitive to knock-down of the CTCF protein by siRNA. Thus, intrinsic looping activity of CTCF sites can nullify LCR function.     

Resveratrol Based Oral Nutritional Supplement Produces Long-Term Beneficial Effects on Structure and Visual Function in Human Patients

Background: Longevinex^® (L/RV) is a low dose hormetic over-the-counter (OTC) oral resveratrol (RV) based matrix of red wine solids, vitamin D₃ and inositol hexaphosphate (IP6) with established bioavailability, safety, and short-term efficacy against the earliest signs of human atherosclerosis, murine cardiac reperfusion injury, clinical retinal neovascularization, and stem cell survival. We previously reported our short-term findings for dry and wet age-related macular degeneration (AMD) patients. Today we report long term (two to three year) clinical efficacy. Methods: We treated three patients including a patient with an AMD treatment resistant variant (polypoidal retinal vasculature disease). We evaluated two clinical measures of ocular structure (fundus autofluorescent imaging and spectral domain optical coherence extended depth choroidal imaging) and qualitatively appraised changes in macular pigment volume. We further evaluated three clinical measures of visual function (Snellen visual acuity, contrast sensitivity, and glare recovery to a cone photo-stress stimulus). Results: We observed broad bilateral improvements in ocular structure and function over a long time period, opposite to what might be expected due to aging and the natural progression of the patient’s pathophysiology. No side effects were observed. Conclusions: These three cases demonstrate that application of epigenetics has long-term efficacy against AMD retinal disease, when the retinal specialist has exhausted other therapeutic modalities.     

In Brief: Genomic imprinting and imprinting diseases

Genomic imprinting is an epigenetic process by which the male and the female germline confer different DNA methylation marks and histone modifications onto specific gene regions, so that one allele of an imprinted gene is active and the other one is silent. Since the dosage of imprinted genes is important for normal development, growth and behaviour, the loss or duplication of the active allele can cause disease. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk     

A case for antibiotic perturbation of the microbiota leading to allergy development

The use of antibiotics to treat pathogenic bacterial infections has been one of the greatest contributions to human health, yet antibiotic use also perturbs the communities of commensal and symbiotic bacteria that reside in the intestine of mammals. The microbiota are critical for normal immune development and for maintaining intestinal homeostasis, and disruption of the microbiota has been linked to the emergence of allergic disease both in humans and in animal models. The evidence and mechanisms for antibiotic-mediated disruptions leading to the onset of allergic disease at mucosal surfaces is discussed, as well as the future challenges for the field. A more complete understanding of the mechanisms by which the intestinal microbiota modulate allergic disease development will allow for interventions to counter the potentially adverse effects of antibiotic treatment on the microbiota.     

Genetic,genomic and epigenetic studies as tools for elucidating disease pathogenesis in primary Sjögren’s syndrome

Primary Sjögren’s syndrome (pSS) is characterized by lymphoid infiltration of lacrimal and salivary glands leading to xerophthalmia and xerostomia. pSS is a complex disease involving both genetic and environmental risk factors. Technological advances over the past 10 years have revolutionized genetics and genomics research enabling high-throughput characterization and analysis of DNA and RNA in patient samples on a genome-wide scale. Further, application of high-throughput methods for characterization of epigenetic variation, such as DNA methylation status, is increasingly being applied to AID populations and will likely further define additional risk factors for disease risk and outcome. Main results obtain in pSS through these various approaches are reviewed here.     

Nutrigenetics,nutrigenomics and inflammatory bowel diseases

Inflammatory bowel disease includes ulcerative colitis and Crohn’s disease, which are both inflammatory disorders of the gastrointestinal tract. Both types of inflammatory bowel disease have a complex etiology, resulting from a genetically determined susceptibility interacting with environmental factors, including the diet and gut microbiota. Genome Wide Association Studies have implicated more than 160 single-nucleotide polymorphisms in disease susceptibility. Consideration of the different pathways suggested to be involved implies that specific dietary interventions are likely to be appropriate, dependent upon the nature of the genes involved. Epigenetics and the gut microbiota are also responsive to dietary interventions. Nutrigenetics may lead to personalized nutrition for disease prevention and treatment, while nutrigenomics may help to understand the nature of the disease and individual response to nutrients.