Wnt3a信号通路通过JMJD6的表观遗传修饰参与神经病理性疼痛

目的：探讨Wnt3a通过Jumonji C结构域6( Jumonji C domain 6,JMJD6)的表观遗传修饰在神经病理性疼痛 中发挥作用的机制。方法：将SD大鼠分为4组：Sham组,慢性缩窄性损伤(chronic constriction injury,CCI)组,CCI+阴性慢病毒表达载体(LV-NC)组;CCI+慢病毒过表达载体(LV-JMJD6)组。构建SD大鼠坐骨神经CCI模型和JMJD6慢病毒 表达载体。CCI术后第3天通过鞘内导管给药,按照分组分别给予生理盐水和含慢病毒的试剂(病毒滴度1×108 TU/mL) 各20 μL。监测大鼠的机械缩足阈值(paw withdrawal mechanical threshold,PWMT)和热缩足潜伏期(paw withdrawal thermal latency,PWTL),并运用蛋白质印迹法检测脊髓水平Wnt3a及NR2B蛋白的表达变化,免疫共沉淀检测JMJD6与Wnt3a之间是否存在直接相互作用。结果：与Sham组相比,CCI术后各组大鼠的PWMT明显降低和PWTL明显缩短(P<0.05)。与CCI组和CCI+LV-NC组相比,CCI+LV-JMJD6组的PWMT在术后第10和14天明显升高,PWTL在术后第14 天明显延长(P<0.05)。CCI术后第14天,CCI组及CCI+LV-NC组Wnt3a和NR2B蛋白表达水平较Sham组明显升高,鞘内注 射慢病毒载体后, CCI+LV-JMJD6组的Wnt3a和NR2B蛋白表达水平较CCI+LV-NC组降低(P<0.05)。免疫共沉淀结果显示Wnt3a与JMJD6之间无直接相互作用。结论：Wnt3a参与调节神经病理性疼痛,其作用可能与JMJD6的表观遗传修饰相关,两者可能通过间接相互作用进行调节。     

Gene–environment interactions in the aetiology of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a disease that displays a multitude of symptoms and a vast array of autoantibodies. The disease course may vary substantially between patients. The current understanding of SLE aetiology includes environmental factors acting on a genetically prone individual during an undetermined time period resulting in autoimmunity and finally surpassing that individual's disease threshold. Genetic differences and environmental factors may interact specifically in the pathogenetic processes and may influence disease development and modify the disease course. Identification of these factors and their interactions in the pathogenesis of SLE is vital in understanding the disease and may contribute to identify new treatment targets and perhaps also aid in disease prevention. However, there are several problems that need to be overcome, such as the protracted time frame of environmental influence, time dependent epigenetic alterations and the possibility that different pathogenetic pathways may result in a similar disease phenotype. This is mirrored by the relatively few studies that suggest specific gene-environment interactions. These include an association between SLE diagnosis and glutathion S-transferase gene variants combined with occupational sun exposure as well as variants of the N-acetyl transferase gene in combination with either aromatic amine exposure or hydralazine. With increased knowledge on SLE pathogenesis, the role of environmental factors and their genetic interactions may be further elucidated.     

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????Salivary gland tumor is one of the most common tumors in head and neck region with a great variety of morphology and biological behavior. Surgical operation is the major choice of salivary gland tumors. However?? except the benign and low-grade malignant tumors?? most salivary malignancies are in lack of specific treatment and the recurrent and metastic frequency is pretty high. Epigenetic study has become a hot spot of cancer research in recent years and one of widely studied field is the DNA promoter methylation. Our current article intends to discuss the possible application of DNA promoter methylation in the development??treatment and prognosis of salivary gland tumors.     

Mercury biomarkers and DNA methylation among michigan dental professionals

Modification of the epigenome may be a mechanism underlying toxicity and disease following chemical exposure. Animal and human data suggest that mercury (Hg) impacts DNA methylation. We hypothesize that methylmercury and inorganic Hg exposures from fish consumption and dental amalgams, respectively, may be associated with altered DNA methylation at global repetitive elements (long interspersed elements, LINE‐1) and candidate genes related to epigenetic processes (DNMT1) and protection against Hg toxicity (SEPW1, SEPP1). Dental professionals were recruited at Michigan Dental Association (MDA) meetings in 2009 and 2010. Subjects (n = 131) provided survey data (e.g. exposure sources, demographics) and biological samples for Hg measurement and epigenetic analysis. Total Hg was quantified via atomic absorption spectrophotometry in hair and urine, indicative of methylmercury and inorganic Hg exposures, respectively. Global repetitive and candidate gene methylation was quantified via pyrosequencing of bisulfite converted DNA isolated from buccal mucosa. Hair Hg (geometric mean (95% CI): 0.37 (0.31–0.44) µg/g) and urine Hg (0.70 (0.60–0.83) µg/L) were associated with sources of exposure (fish consumption and dental amalgams, respectively). Multivariable linear regression revealed a trend of SEPP1 hypomethylation with increasing hair Hg levels, and this was significant (P < 0.05) among males. The trend remained when excluding non‐dentists. No significant relationships between urine Hg and DNA methylation were observed. Thus, in a limited cohort, we identified an association between methylmercury exposure and hypomethylation of a potentially labile region of the genome (SEPP1 promoter), and this relationship was gender specific. Environ. Mol. Mutagen. 54:195–203, 2013. © 2013 Wiley Periodicals, Inc.     

Using zebrafish as a model to study the role of epigenetics in hearing loss

Introduction: The rapid progress of bioinformatics and high-throughput screening techniques in recent years has led to the identification of many candidate genes and small-molecule drugs that have the potential to make significant contributions to our understanding of the developmental and pathological processes of hearing, but it remains unclear how these genes and regulatory factors are coordinated. Increasing evidence suggests that epigenetic mechanisms are essential for establishing gene expression profiles and likely play an important role in the development of inner ear and in the pathology of hearing-associated diseases. Zebrafish are a valuable and tractable in vivo model organism for monitoring changes in the epigenome and for identifying new epigenetic processes and drug molecules that can influence vertebrate development.

Areas covered: In this review, the authors focus on zebrafish as a model to summarize recent findings concerning the roles of epigenetics in the development, regeneration, and protection of hair cells.

Expert opinion: Using the zebrafish model in combination with high-throughput screening and genome-editing technologies to investigate the function of epigenetics in hearing is crucial to help us better understand the molecular and genetic mechanisms of auditory development and function. It will also contribute to the development of new strategies to restore hearing loss.     

Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview

Introduction: Epigenetic mechanisms of gene regulatory control play fundamental roles in developmental morphogenesis, and, as more recently appreciated, are heavily implicated in the onset and progression of neoplastic disease, including cancer. Many epigenetic mechanisms are therapeutically targetable, providing additional incentive for understanding of their contribution to cancer and other types of neoplasia.

Areas covered: The Jumonji-domain histone demethylase (JHDM) family exemplifies many of the above traits. This review summarizes the current state of knowledge of the functions and pharmacologic targeting of JHDMs in cancer and other neoplastic processes, with an emphasis on diseases affecting the pediatric population.

Expert opinion: To date, the JHDM family has largely been studied in the context of normal development and adult cancers. In contrast, comparatively few studies have addressed JHDM biology in cancer and other neoplastic diseases of childhood, especially solid (non-hematopoietic) neoplasms. Encouragingly, the few available examples support important roles for JHDMs in pediatric neoplasia, as well as potential roles for JHDM pharmacologic inhibition in disease management. Further investigations of JHDMs in cancer and other types of neoplasia of childhood can be expected to both enlighten disease biology and inform new approaches to improve disease outcomes.     

Protein Content and Methyl Donors in Maternal Diet Interact to Influence the Proliferation Rate and Cell Fate of Neural Stem Cells in Rat Hippocampus

Maternal diet during pregnancy and early postnatal life influences the setting up of normal physiological functions in the offspring. Epigenetic mechanisms regulate cell differentiation during embryonic development and may mediate gene/environment interactions. We showed here that high methyl donors associated with normal protein content in maternal diet increased the in vitro proliferation rate of neural stem/progenitor cells isolated from rat E19 fetuses. Gene expression on whole hippocampi at weaning confirmed this effect as evidenced by the higher expression of the Nestin and Igf2 genes, suggesting a higher amount of undifferentiated precursor cells. Additionally, protein restriction reduced the expression of the insulin receptor gene, which is essential to the action of IGFII. Inhibition of DNA methylation in neural stem/progenitor cells in vitro increased the expression of the astrocyte-specific Gfap gene and decreased the expression of the neuron-specific Dcx gene, suggesting an impact on cell differentiation. Our data suggest a complex interaction between methyl donors and protein content in maternal diet that influence the expression of major growth factors and their receptors and therefore impact the proliferation and differentiation capacities of neural stem cells, either through external hormone signals or internal genomic regulation.     

Cancer–germline antigen vaccines and epigenetic enhancers: future strategies for cancer treatment

Importance of the field: Immunotherapy holds great potential for disseminated cancer, and cancer–germline (CG) antigens are among the most promising tumor targets. They are widely expressed in different cancer types and are essentially tumor-specific, since their expression in normal tissues is largely restricted to immune-privileged sites. Although the therapeutic potential of these antigens may be compromised by their highly heterogeneous expression in many tumors and low frequency in some cancers, recent developments suggest that tumor-cell-selective enhancement of CG antigen gene expression can be achieved using epigenetic modifiers.

Areas covered in this review: We provide an overview of the potential of CG antigens as targets for cancer immunotherapy, including advantages and disadvantages. We also discuss the current state of development of CG antigen vaccines, and the potential synergistic effect of combining CG antigen immunotherapeutic strategies with epigenetic modifiers.

What the reader will gain: The reader will gain an overview of the past, present and future role of CG antigens in cancer immunotherapy.

Take home message: Chemoimmunotherapy using epigenetic drugs and CG antigen vaccines may be a useful approach for treating cancer.