A systematic review of humoral immune responses against tumor antigens

This review summarizes studies on humoral immune responses against tumor-associated antigens (TAAs) with a focus on antibody frequencies and the potential diagnostic, prognostic, and etiologic relevance of antibodies against TAAs. We performed a systematic literature search in Medline and identified 3,619 articles on humoral immune responses and TAAs. In 145 studies, meeting the inclusion criteria, humoral immune responses in cancer patients have been analyzed against over 100 different TAAs. The most frequently analyzed antigens were p53, MUC1, NY-ESO-1, c-myc, survivin, p62, cyclin B1, and Her2/neu. Antibodies against these TAAs were detected in 0–69% (median 14%) of analyzed tumor patients. Antibody frequencies were generally very low in healthy individuals, with the exception of few TAAs, especially MUC1. For several TAAs, including p53, Her2/neu, and NY-ESO-1, higher antibody frequencies were reported when tumors expressed the respective TAA. Antibodies against MUC1 were associated with a favorable prognosis while antibodies against p53 were associated with poor disease outcome. These data suggest different functional roles of endogenous antibodies against TAAs. Although data on prediagnostic antibody levels are scarce and antibody frequencies for most TAAs are at levels precluding use in diagnostic assays for cancer early detection, there is some promising data on achieving higher sensitivity for cancer detection using panels of TAAs. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Perspectives on the discovery of small-molecule modulators for epigenetic processes

Epigenetic gene regulation is a critical process controlling differentiation and development, the malfunction of which may underpin a variety of diseases. In this article, we review the current landscape of small-molecule epigenetic modulators including drugs on the market, key compounds in clinical trials, and chemical probes being used in epigenetic mechanistic studies. Hit identification strategies for the discovery of small-molecule epigenetic modulators are summarized with respect to writers, erasers, and readers of histone marks. Perspectives are provided on opportunities for new hit discovery approaches, some of which may define the next generation of therapeutic intervention strategies for epigenetic processes.     

体细胞核重编程中表观遗传学的研究进展

促使体细胞核重编程的方法很多,除了传统的体细胞核移植方法外,科学家们努力寻求从法律、道德、伦理等方面更易被人们接受的新方法.近年来多能干细胞与体细胞融合、多能细胞的抽提物与体细胞共孵育以及将编码多潜能因子的基因导入体细胞中等方法都能使体细胞核发生重新编程,将已分化的体细胞转变为一种全能的胚胎状态.主要论述了生殖细胞及早期胚胎、体细胞核移植和其他形式的体细胞核重编程的表观遗传学的改变,对表观遗传学的深入研究将有助于我们进一步了解体细胞核重编程的机制,从而不断完善各种技术促进供体核的重新编程,使其更好地应用于基础研究和生产实践.     

Epigenetic inheritance and plant evolution

Being sessile organisms, plants show a high degree of developmental plasticity to cope with a constantly changing environment. While plasticity in plants is largely controlled genetically, recent studies have demonstrated the importance of epigenetic mechanisms, especially DNA methylation, for gene regulation and phenotypic plasticity in response to internal and external stimuli. Induced epigenetic changes can be a source of phenotypic variations in natural plant populations that can be inherited by progeny for multiple generations. Whether epigenetic phenotypic changes are advantageous in a given environment, and whether they are subject to natural selection is of great interest, and their roles in adaptation and evolution are an area of active research in plant ecology. This review is focused on the role of heritable epigenetic variation induced by environmental changes, and its potential influence on adaptation and evolution in plants.     

Protein arrays as tools for serum autoantibody marker discovery in cancer

Protein array technology has begun to play a significant role in the study of protein–protein interactions and in the identification of antigenic targets of serum autoantibodies in a variety of autoimmune disorders. More recently, this technology has been applied to the identification of autoantibody signatures in cancer.The identification of tumour-associated antigens (TAAs) recognised by the patient's immune response represents an exciting approach to identify novel diagnostic cancer biomarkers and may contribute towards a better understanding of the molecular mechanisms involved. Circulating autoantibodies have not only been used to identify TAAs as diagnostic/prognostic markers and potential therapeutic targets, they also represent excellent biomarkers for the early detection of tumours and potential markers for monitoring the efficacy of treatment. Protein array technology offers the ability to screen the humoral immune response in cancer against thousands of proteins in a high throughput technique, thus readily identifying new panels of TAAs. Such an approach should not only aid in improved diagnostics, but has already contributed to the identification of complex autoantibody signatures that may represent disease subgroups, early diagnostics and facilitated the analysis of vaccine trials.     

Differential Expression of Epigenetic Modulators During Human Embryonic Stem Cell Differentiation

Although the progression of aging and the diseases associated with it are extensively studied, little is known about the initiation of the aging process. Telomerase is down-regulated early in embryonic differentiation, thereby contributing to telomeric attrition and aging. The mechanisms underlying this inhibition remain elusive, but epigenetic studies in differentiating human embryonic stem (hES) cells could give clues about how and when DNA methylation and histone deacetylation work together to contribute to the inactivation of hTERT, the catalytic subunit of telomerase, at the onset of the aging process. We have confirmed the differentiation status of cultured hES colonies with morphological assessment and immunohistochemical stainings for pluripotent stem cells. In hES cells with varying degrees of differentiation, we have shown a stronger association between hES differentiation and expression of the epigenetic regulators DNMT3A and DNMT3B than between genetic modulators of differentiation such as c-MYC. We also propose a new model system for analyses of stem cell regions, which are differentially down-regulating the expression of hTERT and the actions of epigenetic modulators such as the DNMTs and histone methyltransferases.     

Environmental epigenetic modifications and reprogramming-recalcitrant genes

The term “environmental epigenetic modifications” refers to alterations in phenotype triggered by environmental stimuli via epigenetic mechanisms. Epidemiologic and animal model studies show that a subset of such environmental epigenetic marks may affect susceptibility to chronic diseases. A growing body of evidence regarding incompleteness of reprogramming indicates that the potential retention of pathogenic environmental epigenetics in human induced pluripotent stem cells (iPSCs) should be seriously considered. Given this possibility, the optimization of methods for the generation of human induc pluripotent stem cells may require the identification of epigenetically appropriate somatic cell sources. Similarly, techniques for controlling epigenetic modification by environmental factors may also play a critical role in the development of epigenetically stable sources of pluripotent stem cells.     

Cell-to-cell and long-distance siRNA movement in plants: mechanisms and biological implications

In plants, once triggered within a single-cell type, transgene-mediated RNA-silencing can move from cell-to-cell and over long distances through the vasculature to alter gene expression in tissues remote form the primary sites of its initiation. Although, transgenic approaches have been instrumental to genetically decipher the components and channels required for mobile silencing, the possible existence and biological significance of comparable endogenous mobile silencing pathways has remained an open question. Here, we summarize the results from recent studies that shed light on the molecular nature of the nucleic acids involved and on existing endogenous mechanisms that allow long-distance gene regulation and epigenetic modifications. We further elaborate on these and other results to propose a unified view of various non-cell autonomous RNA silencing processes that appear to differ in their genetic requirement and modes of perpetuation in plants.     

Epigenetic modulators for brain cancer stem cells: Implications for anticancer treatment

Primary malignant brain tumors are a major cause of morbidity and mortality in both adults and children, with a dismal prognosis despite multimodal therapeutic approaches. In the last years, a specific subpopulation of cells within the tumor bulk, named cancer stem cells(CSCs) or tumor-initiating cells, have been identified in brain tumors as responsible for cancer growth and disease progression. Stemness features of tumor cells strongly affect treatment response, leading to the escape from conventional therapeutic approaches and subsequently causing tumor relapse. Recent research efforts have focused at identifying new therapeutic strategies capable of specifically targeting CSCs in cancers by taking into consideration their complex nature. Aberrant epigenetic machinery plays a key role in the genesis and progression of brain tumors as well as inducing CSC reprogramming and preserving CSC characteristics. Thus, reverting the cancer epigenome can be considered a promising therapeutic strategy. Three main epigenetic mechanisms have been described: DNA methylation, histone modifications, and non-coding RNA, particularly micro RNAs. Each of these mechanisms has been proven to be targetable by chemical compounds, known as epigeneticbased drugs or epidrugs, that specifically target epigenetic marks. We review here recent advances in the study of epigenetic modulators promoting and sustaining brain tumor stem-like cells. We focus on their potential role in cancer therapy.     

Astrocyte-specific expression patterns associated with the PDGF-induced glioma microenvironment

Background

The tumor microenvironment contains normal, non-neoplastic cells that may contribute to tumor growth and maintenance. Within PDGF-driven murine gliomas, tumor-associated astrocytes (TAAs) are a large component of the tumor microenvironment. The function of non-neoplastic astrocytes in the glioma microenvironment has not been fully elucidated; moreover, the differences between these astrocytes and normal astrocytes are unknown. We therefore sought to identify genes and pathways that are increased in TAAs relative to normal astrocytes and also to determine whether expression of these genes correlates with glioma behavior.

Methodology/Principal Findings

We compared the gene expression profiles of TAAs to normal astrocytes and found the Antigen Presentation Pathway to be significantly increased in TAAs. We then identified a gene signature for glioblastoma (GBM) TAAs and validated the expression of some of those genes within the tumor. We also show that TAAs are derived from the non-tumor, stromal environment, in contrast to the Olig2+ tumor cells that constitute the neoplastic elements in our model. Finally, we validate this GBM TAA signature in patients and show that a TAA-derived gene signature predicts survival specifically in the human proneural subtype of glioma.

Conclusions/Significance

Our data identifies unique gene expression patterns between populations of TAAs and suggests potential roles for stromal astrocytes within the glioma microenvironment. We show that certain stromal astrocytes in the tumor microenvironment express a GBM-specific gene signature and that the majority of these stromal astrocyte genes can predict survival in the human disease.     

The use of diversity profiling to characterize chemical modulators of the histone deacetylases

Target specificity and off-target liabilities are routinely monitored during the early phases of drug discovery for most kinase projects. Typically these criteria are evaluated using a profiling panel comprised of a diverse collection of in vitro kinase assays and relates compound structure to potency and selectivity. The success of these efforts has led to the design of similar panels for phosphatase, protease, and epigenetic targets. Here the implementation of an epigenetic profiling panel, comprised of eleven histone deacetylases (HDACs) and one histone acetyltransferase (HAT), was used to evaluate chemical modulators of these enzymes. HDAC inhibitors (HDACi) such as sodium butyrate and trichostatin A demonstrate diverse biological effects which have led to broad speculation about their therapeutic potential in multiple disease states. Some HDACi have demonstrated tumor suppression in vivo and recently Zolinza was the first HDACi approved by the FDA for the treatment of cutaneous T-cell lymphoma. While HDACi have demonstrated therapeutic utility, many of the first generation compounds are pan-inhibitors. Thus, use of an HDAC profiling panel will be essential in achieving isoform specificity of the next generation of inhibitors. To this end, twenty-one compounds, twelve of which are known to have activities against the HDACs, were tested to evaluate the utility of the epigenetic panel. Additionally, these compounds were tested against a larger 72 member enzyme panel comprised of kinase, phosphatase and protease activities. This effort represents the first time these compounds have been profiled with such a broad range of biochemical activities.     

X-chromosome inactivation in development and cancer

X-chromosome inactivation represents an epigenetics paradigm and a powerful model system of facultative heterochromatin formation triggered by a non-coding RNA, Xist, during development. Once established, the inactive state of the Xi is highly stable in somatic cells, thanks to a combination of chromatin associated proteins, DNA methylation and nuclear organization. However, sporadic reactivation of X-linked genes has been reported during ageing and in transformed cells and disappearance of the Barr body is frequently observed in cancer cells. In this review we summarise current knowledge on the epigenetic changes that accompany X inactivation and discuss the extent to which the inactive X chromosome may be epigenetically or genetically perturbed in breast cancer.     

Epigenetic modifications of histones during osteoblast differentiation

In bone biology, epigenetics plays a key role in mesenchymal stem cells' (MSCs) commitment towards osteoblasts. It involves gene regulatory mechanisms governed by chromatin modulators. Predominant epigenetic mechanisms for efficient osteogenic differentiation include DNA methylation, histone modifications, and non-coding RNAs. Among these mechanisms, histone modifications critically contribute to altering chromatin configuration. Histone based epigenetic mechanisms are an essential mediator of gene expression during osteoblast differentiation as it directs the bivalency of the genome. Investigating the importance of histone modifications in osteogenesis may lead to the development of epigenetic-based remedies for genetic disorders of bone. Hence, in this review, we have highlighted the importance of epigenetic modifications such as post-translational modifications of histones, including methylation, acetylation, phosphorylation, ubiquitination, and their role in the activation or suppression of gene expression during osteoblast differentiation. Further, we have emphasized the future advancements in the field of epigenetics towards orthopaedical therapeutics.     

Moonlighting activity of the epigenetic machinery restrains infection

Intracellular bacterial pathogens have evolved a range of mechanisms, including manipulation of the host cell epigenetic machinery and host cell gene expression rewiring, to parasitize and thrive inside host phagocytes. A new study in The EMBO Journal (Yaseen et al, 2018 ) reports that, conversely, host macrophages can use epigenetic modulators to modify the cell surface of invading pathogens and counteract infection. This study opens new avenues to better understand host–pathogen interactions and to develop novel, more effective antimicrobial strategies.     

The role of arginine methylation in the DNA damage response

Post-translational modifications are well-known modulators of DNA damage signaling and epigenetic gene expression. Protein arginine methylation is a covalent modification that results in the addition of methyl groups to the nitrogen atoms of the arginine side chains and is catalyzed by a family of protein arginine methyltransferases (PRMTs). In the past, arginine methylation was mainly observed on abundant proteins such as RNA-binding proteins and histones, but recent advances have revealed a plethora of arginine methylated proteins implicated in a variety of cellular processes including RNA metabolism, epigenetic regulation and DNA repair pathways. Herein, we discuss these recent advances, focusing on the role of PRMTs in DNA damage signaling and its importance for maintaining genomic stability.