Epigenetic Effectors: New Treatments for Neurological Disease

The Neuron Restrictive Silencer Factor (NRSF) is the well-known master transcriptional repressor of the neuronal phenotype. Research to date has shown that it is an important player in the growth and development of the nervous system. Its role in the maturation of neural precursor cells to adult neurons has been well characterized in stem cell models. While much has been characterized from a developmental perspective, research is revealing that NRSF plays a role in various neurological diseases, ranging from neurodegenerative, neuropsychiatric, to cancer. Dysregulation of NRSF activity disrupts downstream gene expression that is responsible for neuronal cell homeostasis in several models that contribute to pathologic states. Interestingly, it is now becoming apparent that the dysregulation of NRSF contributes to neurological disease through epigenetic mechanisms. Although NRSF itself is a transcription factor, its major effectors are chromatin modifiers. At the level of epigenetics, changes in NRSF activity have been well characterized in models of neuropathic pain and epilepsy. Better understanding of the epigenetic basis of brain diseases has led to design and use of small molecules that can prevent NRSF from repressing gene expression by neutralizing its interactions with its chromatin remodelers. This review will address the basic function of NRSF and its cofactors, investigate their mechanisms, then explore how their dysfunction can cause disease states. This review will also address research on NRSF as a therapeutic target and delve into new therapeutic strategies that focus on disrupting NRSF's ability to recruit chromatin remodelers.

Epigenetics of Male Fertility: Effects on Assisted Reproductive Techniques

During the last decades the study of male infertility & the introduction of the assisted reproductive techniques (ARTs) has allowed to understand that normal sperm parameters do not always predict fertilization. Sperm genetic components could play an important role in the early stages of embryonic development. Based on these acquisitions, several epigenetic investigations have been developed on spermatozoa, with the aim of understanding the multifactorial etiology of male infertility & of showing whether embryonic development may be influenced by sperm epigenetic abnormalities. This article reviews the possible epigenetic modifications of spermatozoa & their effects on male fertility, embryonic development & ART outcome. It focuses mainly on sperm DNA methylation, chromatin remodeling, histone modifications & RNAs.

A session "Epigenetics in reproductive health" going to be held at Vienna.

The Development of Epigenetics & Related Inhibitors for Targeted Drug Design in Cancer Therapy

Epigenetics process is the heritable change in gene function that does not involve changes in the DNA sequence. Until now, several types of epigenetic mechanisms have been characterized, including DNA methylation, histone modification (acetylation, methylation, etc.) nucleosome remodeling, and noncoding RNAs. With the biological investigations of these modifiers, some of them are identified as promoters in the process of various diseases, such as cancer, cardiovascular disease and virus infection. Epigenetic changes may serve as potential "first hits" for tumorigenesis. Hence, targeting epigenetic modifiers is being considered as a promising way for disease treatment. To date, six agents in two epigenetic target classes (DNMT and HDAC) have been approved by the US Food and Drug Administration (FDA). Most of these drugs are applied in leukemia, lymphoma therapy, or are combined with other drugs for the treatment of solid tumor. Due to the rapid development of epigenetics and epigenetics targeted drugs, it is becoming an emerging area in targeted drug design.

Epigenetics Market Products & Instrumentation for Absolute quantification of DNA methylation using microfluidic chip-based digital PCR

Hypermethylation of CpG islands in the promoter region of many tumor suppressor genes downregulates their expression & in a result promotes tumorigenesis. Therefore, detection of DNA methylation status is a convenient diagnostic tool for cancer detection. Here, we reported a novel method for the integrative detection of methylation by the microfluidic chip-based digital PCR. This method relies on methylation-sensitive restriction enzyme HpaII, which cleaves the unmethylated DNA strands while keeping the methylated ones intact. After HpaII treatment, the DNA methylation level is determined quantitatively by the microfluidic chip-based digital PCR with the lower limit of detection equal to 0.52%. To validate the applicability of this method, promoter methylation of two tumor suppressor genes (PCDHGB6 and HOXA9) was tested in 10 samples of early stage lung adenocarcinoma and their adjacent non-tumorous tissues. The consistency was observed in the analysis of these samples using our method and a conventional bisulfite pyrosequencing. Combining high sensitivity & low cost, the microfluidic chip-based digital PCR method might provide a promising alternative for the detection of DNA methylation & early diagnosis of epigenetics-related diseases.

Environmental epigenomics and disease susceptibility session at Epigenetics 2019

Epidemiological evidence increasingly suggests that environmental exposures early in development have a role in susceptibility to disease in later life. In addition, some of these environmental effects seem to be passed on through subsequent generations. Epigenetic modifications provide a plausible link between the environment and alterations in gene expression that might lead to disease phenotypes. An increasing body of evidence from animal studies supports the role of environmental epigenetics in disease susceptibility. Furthermore, recent studies have demonstrated for the first time that heritableenvironmentally induced epigenetic modifications underlie reversible transgenerational alterations in phenotype. Methods are now becoming available to investigate the relevance of these phenomena to human disease.

Cytotoxicity & Transcriptomic Analysis of Silver Nanoparticles in Mouse Embryonic Fibroblast Cells

The rapid development of nanotechnology has led to the use of silver nanoparticles (AgNPs) in biomedical applications, including antibacterial, antiviral, anti-inflammatory & anticancer therapies. The molecular mechanism of AgNPs-induced cytotoxicity has not been studied thoroughly using a combination of cellular assays & RNA sequencing (RNA-Seq) analysis. In this study, we prepared AgNPs using myricetin, an anti-oxidant polyphenol & studied their effects on NIH3T3 mouse embryonic fibroblasts as an in vitro model system to explore the potential biomedical applications of AgNPs. AgNPs induced loss of cell viability and cell proliferation in a dose-dependent manner, as evident by increased leakage of lactate dehydrogenase (LDH) from cells. Reactive oxygen species (ROS) were a potential source of cytotoxicity. AgNPs also incrementally increased oxidative stress & the level of malondialdehyde, depleted glutathione and superoxide dismutase, reduced mitochondrial membrane potential and adenosine triphosphate (ATP), and caused DNA damage by increasing the level of 8-hydroxy-2'-deoxyguanosine and the expressions of the p53 and p21 genes in NIH3T3 cells. Thus, activation of oxidative stress may be crucial for NIH3T3 cytotoxicity. Interestingly, gene ontology (GO) term analysis revealed alterations in epigenetics-related biological processes including nucleosome assembly & DNA methylation due to AgNPs exposure. This study is the first demonstration that AgNPs can alter bulk histone gene expression. Therefore, our genome-scale study suggests that the apoptosis observed in NIH3T3 cells treated with AgNPs is mediated by the repression of genes required for cell survival and the aberrant enhancement of nucleosome assembly components to induce apoptosis.

Session taking pace at Vienna: https://epigenetics.expertconferences.org/events-list/epigenetics-in-biotechnology-developmental-biology

Epigenetic regulation of FOXA2 in endometrial cancer

FOXA2 is a pioneer transcription factor that plays an important role in normal development and in adult tissues. The Cancer Genome Atlas project identified FOXA2 as a “significantly mutated gene” in endometrial cancer, with the majority of mutations being loss-of-function defects. Epigenetic silencing of genes associated with methylation of CpG-rich promoter regions is seen in cancers. We sought to analyze the FOXA2promoter region for methylation and to determine the relationship between methylation and mRNA and protein expression.

Epigenetics 2019

https://epigenetics.expertconferences.org/events-list/epigenetics