Epigenetic alterations and their clinical implications in esophageal squamous cell carcinoma

Alterations in the regulation of gene expression that do not involve a change in the DNA sequence have been increasingly recognized as an important key event of carcinogenesis, referred to as “epigenetic” changes. Major epigenetic mechanisms include the methylation of cytosines in DNA, changes of histone and chromatin structure by covalent posttranslational modifications of histone proteins and alterations in the expression of microRNAs. These epigenetic alterations have also been identified in esophageal squamous cell carcinoma (ESCC). In this brief review, we will discuss DNA hypermethylation of the tumor suppressor gene promoters, histone modifications including histone acetylation/deacetylation and histone methylation and microRNAs in ESCC. Clinical implications of these epigenetic alterations in ESCC will be also discussed.     

A methyl-deficient diet modifies histone methylation and alters Igf2 and H19 repression in the prostate

BACKGROUND: Folate and methyl-group deficiency has been linked to prostate cancer susceptibility, yet the mechanisms underlying these observations are incompletely understood. The region of the genome containing the imprinted genes insulin-like growth factor 2 (Igf2) and H19, both of which display oncogenic functions, may be particularly sensitive to environmental influences. METHODS: To determine whether a methyl-deficient diet impacts epigenetic controls at the Igf2-H19 locus, we placed C57BL/6 mice containing a polymorphism at the imprinted Igf2-H19 locus on a choline and methionine deficient (CMD) diet. We interrogated this locus for expression and epigenetic changes in prostate tissues. RESULTS: A significant increase in both Igf2 and H19 expression was found in CMD prostate tissues compared to controls. These expression changes were reversible with shorter exposure to the CMD diet. Chromatin immunoprecipitation (ChIP) revealed significant decreases in repressive histone modifications (dimethyl-H3K9) within the H19 promoter, as well as Igf2 P2 and P3 promoters. DNA methylation within these promoters was not altered. No significant change in Igf2 or H19 imprinting was observed. CONCLUSIONS: These findings highlight the plasticity of the epigenome in an epithelial organ vulnerable to neoplastic change. They further suggest that chromatin modifications are more susceptible to methyl-deficient diets than DNA methylation at this locus.     

Epigenetics in prostate cancer: biologic and clinical relevance

Context

Prostate cancer (PCa) is one of the most common human malignancies and arises through genetic and epigenetic alterations. Epigenetic modifications include DNA methylation, histone modifications, and microRNAs (miRNA) and produce heritable changes in gene expression without altering the DNA coding sequence.

Objective

To review progress in the understanding of PCa epigenetics and to focus upon translational applications of this knowledge.

Evidence acquisition

PubMed was searched for publications regarding PCa and DNA methylation, histone modifications, and miRNAs. Reports were selected based on the detail of analysis, mechanistic support of data, novelty, and potential clinical applications.

Evidence synthesis

Aberrant DNA methylation (hypo- and hypermethylation) is the best-characterized alteration in PCa and leads to genomic instability and inappropriate gene expression. Global and locus-specific changes in chromatin remodeling are implicated in PCa, with evidence suggesting a causative dysfunction of histone-modifying enzymes. MicroRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen receptor signaling and apoptosis. There are important connections between common genetic alterations (eg, E twenty-six fusion genes) and the altered epigenetic landscape. Owing to the ubiquitous nature of epigenetic alterations, they provide potential biomarkers for PCa detection, diagnosis, assessment of prognosis, and post-treatment surveillance.

Conclusions

Altered epigenetic gene regulation is involved in the genesis and progression of PCa. Epigenetic alterations may provide valuable tools for the management of PCa patients and be targeted by pharmacologic compounds that reverse their nature. The potential for epigenetic changes in PCa requires further exploration and validation to enable translation to the clinic.     

Cross-talk Between Histone and DNA Methylation Mediates Bone Loss in Hind Limb Unloading

Bone loss induced by mechanical unloading is a common skeletal disease, but the precise mechanism remains unclear. The current study investigated the role of histone methylation, a key epigenetic marker, and its cross-talk with DNA methylation in bone loss induced by mechanical unloading. The expression of G9a, ubiquitin-like with PHD and ring finger domains 1 (UHRF1), and DNA methylation transferase 1 (DNMT1) were increased in hind limb unloading (HLU) rats. This was accompanied by an increased level of histone H3 lysine 9 (H3K9) di-/tri-methylation at lncH19 promoter. Then, alteration of G9a, DNMT1, or UHRF1 expression significantly affected lncH19 level and osteogenic activity in UMR106 cells. Osteogenic gene expression and matrix mineralization were robustly promoted after simultaneous knockdown of G9a, DNMT1, and UHRF1. Furthermore, physical interactions of lncH19 promoter with G9a and DNMT1, as well as direct interactions among DNMT1, G9a, and UHRF1 were detected. Importantly, overexpression of DNMT1, G9a, or UHRF1, respectively, resulted in enrichment of H3K9me2/me3 and 5-methylcytosine at lncH19 promoter. Finally, in vivo rescue experiments indicated that knockdown of DNMT1, G9a, or UHRF1 significantly relieved bone loss in HLU rats. In conclusion, our research demonstrated the critical role of H3K9 methylation and its cross-talk with DNA methylation in regulating lncH19 expression and bone loss in HLU rats. Combined targeting of DNMT1, G9a, and UHRF1 could be a promising strategy for the treatment of bone loss induced by mechanical unloading. © 2021 American Society for Bone and Mineral Research (ASBMR).     

pSi2.1-G9a-siRNA 诱导人胆管癌细胞RASSF1A 基因脱甲基化

目的 分析组蛋白甲基转移酶Gga特异性siRNA真核表达质粒pSi2.1-G9a-siRNA对人胆管癌细胞株QBC939中RASSF1A基因启动子甲基化及其表达的影响,探讨组蛋白甲基化和DNA甲基化的关系.方法 构建pSi2.1-G9a-siRNA真核表达质粒并转染QBC939细胞,甲基化特异性PCR(MS-PCR)检测RASSF1A启动子甲基化状态的改变,逆转录-聚合酶链反应(RT-PCR)观察RASSF1A mRNA水平变化,Western blot检测RASSF1A蛋白表达.结果 转染pSi2.1-G9a-siRNA后,QBC939细胞中RASSF1A启动子由甲基化状态转变为非甲基化状态;RT-PCR和Western blot结果 显示转染组细胞中分别出现RASSF1A基因的DNA条带(280 bp)和蛋白质条带(40×103),而转染前没有相应条带出现.结论 pSi2.1-G9a-siRNA质粒能够诱导QBC939中RASSF1A启动子去甲基化并恢复表达,提示DNA甲基化在一定程度上受组蛋白甲基化的调控.     

The Epigenetic Landscape of Mammary Gland Development and Functional Differentiation

Most of the development and functional differentiation in the mammary gland occur after birth. Epigenetics is defined as the stable alterations in gene expression potential that arise during development and proliferation. Epigenetic changes are mediated at the biochemical level by the chromatin conformation initiated by DNA methylation, histone variants, post-translational modifications of histones, non-histone chromatin proteins, and non-coding RNAs. Epigenetics plays a key role in development. However, very little is known about its role in the developing mammary gland or how it might integrate the many signalling pathways involved in mammary gland development and function that have been discovered during the past few decades. An inverse relationship between marks of closed (DNA methylation) or open chromatin (DnaseI hypersensitivity, certain histone modifications) and milk protein gene expression has been documented. Recent studies have shown that during development and functional differentiation, both global and local chromatin changes occur. Locally, chromatin at distal regulatory elements and promoters of milk protein genes gains a more open conformation. Furthermore, changes occur both in looping between regulatory elements and attachment to nuclear matrix. These changes are induced by developmental signals and environmental conditions. Additionally, distinct epigenetic patterns have been identified in mammary gland stem and progenitor cell sub-populations. Together, these findings suggest that epigenetics plays a role in mammary development and function. With the new tools for epigenomics developed in recent years, we now can begin to establish a framework for the role of epigenetics in mammary gland development and disease.     

Specialized distribution of the histone methyltransferase ezh2 in the nuclear apical region of round spermatids and its interaction with the histone variant h1t2

The formation of sperm requires tightly regulated gene expression and unique chromatin remodeling. In the present study, we investigated the spermatogenic distribution of the lysine-specific histone H3 methyltransferase Ezh2 in mice. The distribution of Ezh2 was highly regulated with its localization predominantly restricted to round spermatids in the perinuclear acrosome region. This localization is concomitant with the dramatic epigenetic reorganization that occurs during spermiogenesis leading to an extreme compaction of the chromatin. Spermiogenesis involves the incorporation of sperm-specific nuclear proteins, including the testis-specific histone variant H1t2. Using immunofluorescence, Ezh2 was shown to juxtapose H1t2, and an interaction in chromatin was confirmed by immunoprecipitation. These findings suggest that, in the testis, the apical region of the round spermatid nucleus could be a specialized epigenetic region where methylation of histones serves a role in the spermiogenic chromatin remodeling and that Ezh2 might be a key effector of this event.     

神经病理性疼痛的表观遗传学发展方向

背景 神经病理性疼痛(neuropathic pain,NP)是由神经系统的损害或炎症引起的一种常见而特殊的慢性疼痛,以痛觉过敏、异常痛敏和自发痛为特征.目前发病机制不清,发病率逐年上升,处理非常棘手而且目前的治疗方法疗效不佳,是医学领域的挑战性研究课题. 目的 综述表观遗传学在疼痛中的研究状况. 内容 主要对表观遗传学的基本原理、生物学作用以及表观遗传学在疼痛中的研究进展进行综述. 趋向 表观遗传学在NP中的作用将为人们进一步深入阐明疼痛机制提供新的思路,为NP的治疗提供新的策略.     

Epigenetic regulation in the acute kidney injury to chronic kidney disease transition

Epigenetic modifications have emerged as a new, important contributor to gene expression regulation in both normal and pathophysiological conditions. Epigenetics have been studied in many diseases and conditions such as acute kidney injury (AKI), a syndrome with a high prevalence that carries a poor prognosis with increased morbidity and mortality. In addition, it has recently been shown that AKI increases the risk for the development of chronic kidney disease (CKD). The specific molecular mechanisms by which AKI increases the risk of CKD and end stage renal disease (ESRD) remain unknown, although there is new evidence supporting a role of epigenetic changes. The most studied epigenetic regulations in AKI are chromatin compaction, DNA methylation, and histone acetylation/deacetylation. These modifications predominantly increase the production of pro‐inflammatory and profibrotic cytokines such as: monocyte chemoattractant protein‐1 (MCP‐1), complement protein 3 (C3), transforming growth factor β (TGF‐β) that have been shown for perpetuating inflammation, promoting epithelial‐to‐mesenchymal transition (EMT) and ultimately causing renal fibrosis. A review of epigenetic mechanisms, the pathophysiology of AKI and recent studies that implicate epigenetic modifications in AKI and in the transition to CKD are discussed below.     

Genomic surgery for lung cancer

An emerging body of literature indicates that reversible alterations in chromatin structure modulate gene expression during malignant transformation. Chromatin structure is regulated in part by DNA methylation and histone acetylation; these independent yet highly interrelated epigenetic processes are influenced by a variety of signal transduction pathways. The present review highlights recent advances regarding cancer epigenetics, focusing on the potential utilization of chromatin remodeling agents to induce apoptosis and enhance the immunogenicity of thoracic malignancies.