Epigenetic changes associated with inflammation in breast cancer patients treated with chemotherapy

Inflammation has been associated with fatigue during and after various types of breast cancer treatments. We examined whether prior chemotherapy was associated with DNA methylation patterns that could explain persisting inflammation and/or fatigue in women treated for breast cancer. Prior to breast radiation therapy, DNA was extracted from peripheral blood mononuclear cells (PBMCs) of 61 Stage 0-IIIA breast cancer patients who had received partial mastectomy with or without chemotherapy. DNA methylation was assessed at >485,000 CpG sites across the genome along with fatigue and plasma inflammatory markers previously associated with fatigue. Compared to non-chemotherapy-treated, women who had received chemotherapy exhibited significantly decreased methylation at eight CpG sites (p < 1.03 × 10⁻⁷) including four in exon 11 of transmembrane protein 49 (TMEM49), which demonstrated the largest decreases in methylation. Lower methylation at each identified CpG site was associated with increased plasma soluble tumor necrosis factor receptor 2 (sTNFR2) and interleukin (IL)-6 and mediated the relationship between chemotherapy and increases in these inflammatory biomarkers adjusting for multiple clinical and treatment characteristics. sTNFR2, but not CpG methylation status, was correlated with fatigue. Six months after breast radiation therapy, DNA methylation, inflammatory biomarkers and fatigue assessments were repeated in a subset of subjects (N = 39). Reduced methylation in 4 of the 8 identified CpG sites was still observed in chemotherapy versus non-chemotherapy-treated patients, albeit with some decay indicating the dynamic and potentially reversible nature of the changes. Reduced methylation in these 4 CpG sites also continued to correlate with either increased sTNFR2 or IL-6, but not fatigue. In conclusion, prior chemotherapy treatment was associated with decreased methylation of CpG sites in DNA from PBMCs of breast cancer patients, which correlated with increased inflammatory markers prior to and 6 months after radiation therapy. Persisting epigenetic changes secondary to chemotherapy may be one factor that contributes to inflammation and its consequences including cancer-related fatigue in vulnerable breast cancer patients.     

Differential effects of binge methamphetamine injections on the mRNA expression of histone deacetylases (HDACs) in the rat striatum

Methamphetamine use disorder is characterized by recurrent binge episodes. Humans addicted to methamphetamine experience various degrees of cognitive deficits and show evidence of neurodegenerative processes in the brain. Binge injections of METH to rodents also cause significant toxic changes in the brain. In addition, this pattern of METH injections can alter gene expression in the dorsal striatum. Gene expression is regulated, in part, by histone deacetylation. We thus tested the possibility that METH toxic doses might cause changes in the mRNA levels of histone deacetylases (HDACs). We found that METH did produce significant decreases in the mRNA expression of HDAC8, which is a class I HDAC. METH also decreased expression of HDAC6, HDAC9, and HDAC10 that are class II HDACs. The expression of the class IV HDAC, HDAC11, was also suppressed by METH. The expression of Sirt2, Sirt5, and Sirt6 that are members of class III HDACs was also downregulated by METH injections. Our findings implicate changes in HDAC expression may be an early indicator of impending METH-induced neurotoxicity in the striatum. This idea is consistent with the accumulated evidence that some HDACs are involved in neurodegenerative processes in the brain.     

The effects of selected inhibitors of histone modifying enzyme on C6 glioma cells

BackgroundAberrant epigenetic histone modifications are implicated in cancer pathobiology, therefore histone modifying enzymes are emerging targets for anti-cancer therapy. There is a few evidence for deregulation of the histone modifying enzymes in glioblastomas. Glioma treatment is a clinical challenge due to its resistance to current therapies.MethodsThe effect of selected inhibitors on epigenetic modifications and viability of glioma C6 cells were studied using immunofluorescence and MTT metabolism test.ResultsWe found that VPA and TSA increase histone H4 acetylation in glioma cells, while chaetocin and BIX01294 at low concentrations reduce H3K9me3, and 3DZNep decreases H3K27me3. Long-term treatment with some epigenetic inhibitors affects viability of glioma cells.ConclusionsWe established the concentrations of selected inhibitors which in C6 glioma cells inhibit the enzyme activity, but do not decrease cell viability, hence allow to study the role of histone modifications in C6 glioma biology.     

Palmitate-TLR4 signaling regulates the histone demethylase,JMJD3, in macrophages and impairs diabetic wound healing

Chronic macrophage inflammation is a hallmark of type 2 diabetes (T2D) and linked to the development of secondary diabetic complications. T2D is characterized by excess concentrations of saturated fatty acids (SFA) that activate innate immune inflammatory responses, however, mechanism(s) by which SFAs control inflammation is unknown. Using monocyte-macrophages isolated from human blood and murine models, we demonstrate that palmitate (C16:0), the most abundant circulating SFA in T2D, increases expression of the histone demethylase, Jmjd3. Upregulation of Jmjd3 results in removal of the repressive histone methylation (H3K27me3) mark on NFκB-mediated inflammatory gene promoters driving macrophage-mediated inflammation. We identify that the effects of palmitate are fatty acid specific, as laurate (C12:0) does not regulate Jmjd3 and the associated inflammatory profile. Further, palmitate-induced Jmjd3 expression is controlled via TLR4/MyD88-dependent signaling mechanism, where genetic depletion of TLR4 (Tlr4^−/−) or MyD88 (MyD88^−/−) negated the palmitate-induced changes in Jmjd3 and downstream NFκB-induced inflammation. Pharmacological inhibition of Jmjd3 using a small molecule inhibitor (GSK-J4) reduced macrophage inflammation and improved diabetic wound healing. Together, we conclude that palmitate contributes to the chronic Jmjd3-mediated activation of macrophages in diabetic peripheral tissue and a histone demethylase inhibitor-based therapy may represent a novel treatment for nonhealing diabetic wounds.     

Cross-region reduction in 5-hydroxymethylcytosine in Alzheimer's disease brain

Epigenetic processes play a key role in the central nervous system and altered levels of 5-methylcytosine have been associated with a number of neurologic phenotypes, including Alzheimer's disease (AD). Recently, 3 additional cytosine modifications have been identified (5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine), which are thought to be intermediate steps in the demethylation of 5-methylcytosine to unmodified cytosine. Little is known about the frequency of these modifications in the human brain during health or disease. In this study, we used immunofluorescence to confirm the presence of each modification in human brain and investigate their cross-tissue abundance in AD patients and elderly control samples. We identify a significant AD-associated decrease in global 5-hydroxymethylcytosine in entorhinal cortex and cerebellum, and differences in 5-formylcytosine levels between brain regions. Our study further implicates a role for epigenetic alterations in AD.     

Approaches for drawing causal inferences from epidemiological birth cohorts: A review

Large-scale population-based birth cohorts, which recruit women during pregnancy or at birth and follow up their offspring through infancy and into childhood and adolescence, provide the opportunity to monitor and model early life exposures in relation to developmental characteristics and later life outcomes. However, due to confounding and other limitations, identification of causal risk factors has proved challenging and published findings are often not reproducible. A suite of methods has been developed in recent years to minimise problems afflicting observational epidemiology, to strengthen causal inference and to provide greater insights into modifiable intra-uterine and early life risk factors. The aim of this review is to describe these causal inference methods and to suggest how they may be applied in the context of birth cohorts and extended along with the development of birth cohort consortia and expansion of “omic” technologies.     

弥漫大B细胞淋巴瘤的DNA甲基化改变及治疗进展

弥漫大B细胞淋巴瘤(DLBCL)异质性较高,具有不同的临床和病理特征,是成人淋巴瘤的一种常见类型。尽管一部分DLBCL已经可以治愈,但难治和复发患者的治疗仍然具有挑战性。近年来,DNA甲基化等表观遗传修饰成为DLBCL的研究热点。调控甲基化修饰的基因突变及抑癌基因甲基化修饰在DLBCL发病及预后中起到关键作用。本文对DLBCL的DNA甲基化研究进展进行综述。     

肿瘤表观遗传学研究进展

对肿瘤研究的不断深入使人们认识到几乎所有人类肿瘤都是由表观遗传学异常与基因改变共同引起并促进其演变的.表观遗传学改变主要包括DNA甲基化改变和组蛋白修饰,这两种调控模式本身及之间的相互作用网络可导致印记丢失,染色质重塑,非必需重复序列的转录、基因的异常活化以及抑制肿瘤发生和演进基因的异常沉默等,在异常的克隆性增生和癌性增生的级联事件起始中发挥重要作用,在酵母模型中的研究更深入的理解了肿瘤干细胞的定义以及引起肿瘤的相关分子机制.表观遗传学的研究为进一步了解肿瘤的各种特性,优化肿瘤的早期诊断,改善肿瘤的预后提供了新的策略.     

Epigenetic Inactivation of Tumor Suppressor Genes in Hematologic Malignancies

A number of genetic alterations are involved in the development of hematologic malignancies. These alterations include the activation of oncogenes by chromosomal translocation or gene amplification and the inactivation of tumor suppressor genes by gene deletion or mutations. Recently, epigenetic change has been proven to be another important means of inactivating tumor suppressor genes in tumor cells, and hypermethylation of promoter DNA is one of the most important mechanisms. In hematologic malignancies, many kinds of tumor suppressor genes and candidate suppressor genes are epigenetically inactivated. Inactivation of tumor suppressor genes usually occurs in a disease-specific manner and plays important roles in the development and progression of the disease. Some of these alterations have clinical effects on treatment results or the prognoses of the patients.     

电离辐射诱导的DNA甲基化模式改变及其在辐射致癌机制研究中的意义

越来越多的研究已经表明,表观遗传机制在癌症发生发展中扮演了非常重要的角色,但是对于辐射致癌的表观遗传机制的研究仅刚刚起步。本文介绍了表观遗传和一种重要的表观遗传标志——DNA甲基化的相关概念,并综述了近年来人们对电离辐射诱导的DNA甲基化模式改变的研究以及DNA甲基化模式改变在辐射致癌机制研究中的意义。