DNA methylation in cancer and ageing

Epigenetic gene silencing through DNA methylation is now clearly thought to be one of the important steps in the mechanism underlying tumourigenesis. The methylation of several genes increases with age in normal tissues such as the colon. Methylation related to cancer and ageing may lead to new biomarkers and therapeutic concepts for cancer.     

Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level

Using a transgenic approach, we examined distal regulatory elements located in the IL-4 locus and the role of GATA-3 at these elements. The intergenic DNase I hypersensitive sites (HSS) showed strong enhancement, and the intronic enhancer (IE) and HS5/HS5a sites showed weaker enhancement of the IL-4 promoter. Elements in the 3' region of the IL-4 gene contributed to Th2 specificity. All individual enhancers were T cell activation dependent but not Th2 specific, with the exception of IE. However, when these distal elements were combined into a "minilocus," expression was strongly enhanced and Th2 specific. GATA-3 mediated strong enhancement of IL-4 promoter activity in Th1 cells when the promoter was embedded in the minilocus or linked to HSS and IE, demonstrating that GATA-3 acts through these elements to regulate IL-4 gene expression.     

DNA methylation, imprinting and cancer

It is well known that a variety of genetic changes influence the development and progression of cancer. These changes may result from inherited or spontaneous mutations that are not corrected by repair mechanisms prior to DNA replication. It is increasingly clear that so called epigenetic effects that do not affect the primary sequence of the genome also play an important role in tumorigenesis. This was supported initially by observations that cancer genomes undergo changes in their methylation state and that control of parental allele-specific methylation and expression of imprinted loci is lost in several cancers. Many loci acquiring aberrant methylation in cancers have since been identified and shown to be silenced by DNA methylation. In many cases, this mechanism of silencing inactivates tumour suppressors as effectively as frank mutation and is one of the cancer-predisposing hits described in Knudson's two hit hypothesis. In contrast to mutations which are essentially irreversible, methylation changes are reversible, raising the possibility of developing therapeutics based on restoring the normal methylation state to cancer-associated genes. Development of such therapeutics will require identifying loci undergoing methylation changes in cancer, understanding how their methylation influences tumorigenesis and identifying the mechanisms regulating the methylation state of the genome. The purpose of this review is to summarise what is known about these issues.     

DNA甲基化在肿瘤诊断和治疗中应用的研究进展

DNA甲基化是重要的表遗传学修饰方式.启动子区异常高甲基化是抑癌基因表达失活的主要机制之一,与肿瘤的发生密切相关.现重点将DNA异常甲基化研究在临床肿瘤诊断、治疗以及监测等方面的应用及意义作一综述.     

DNA methylation profiles in cancer diagnosis and therapeutics

Cancer initiation and proliferation is regulated by both epigenetic and genetic events with epigenetic modifications being increasingly identified as important targets for cancer research. DNA methylation catalyzed by DNA methyltransferases (DNMTs) is one of the essential epigenetic mechanisms that control cell proliferation, apoptosis, differentiation, cell cycle, and transformation in eukaryotes. Recent progress in epigenetics revealed a deeper understanding of the mechanisms of tumorigenesis and provided biomarkers for early detection, diagnosis, and prognosis in cancer patients. Although DNA methylation biomarker possesses potential contributing to precision medicine, there are still limitations to be overcome before it reaches clinical setting. Hence, the current status of DNA methylation biomarkers was reviewed and the future use in clinic was also predicted.     

DNA甲基化修饰异常与肺癌

DNA甲基化是表观遗传学研究的重要内容之一,与多种肿瘤的发生、发展密切相关。近年研究发现,肺癌相关基因高甲基化及甲基化转移酶的表达异常与肺癌发生有重要关系。了解DNA甲基化修饰异常在肺癌发生机制中的作用,将有助于患者的早期预防、早期诊断和改善预后。     

DNA甲基化与肺癌关系的研究进展

在表观遗传学中,DNA甲基化是最为主要的修饰方法,异常的甲基化会使DNA的转录过程发生异常,进而与肿瘤的发生、发展有着密切的联系。随着甲基化检测方法的快速发展,越来越多的研究发现肺癌中存在DNA的异常甲基化,而且检测甲基化的DNA片段对肺癌的诊断也具有一定意义。不仅如此,某些DNA的甲基化情况与患者的生存时间及复发等情况也密切相关。本文就DNA甲基化在肺癌的诊断、治疗以及预后等方面做一综述。     

ImprintSeq,a novel tool to interrogate DNA methylation at human imprinted regions and diagnose multilocus imprinting disturbance

PurposeDisruptions of genomic imprinting are associated with congenital imprinting disorders (CIDs) and other disease states, including cancer. CIDs are most often associated with altered methylation at imprinted differentially methylated regions (iDMRs). In some cases, multiple iDMRs are affected causing multilocus imprinting disturbances (MLIDs). The availability of accurate, quantitative, and scalable high-throughput methods to interrogate multiple iDMRs simultaneously would enhance clinical diagnostics and research.MethodsWe report the development of a custom targeted methylation sequencing panel that covered most relevant 63 iDMRs for CIDs and the detection of MLIDs. We tested it in 70 healthy controls and 147 individuals with CIDs. We distinguished loss and gain of methylation per differentially methylated region and classified high and moderate methylation alterations.ResultsAcross a range of CIDs with a variety of molecular mechanisms, ImprintSeq performed at 98.4% sensitivity, 99.9% specificity, and 99.9% accuracy (when compared with previous diagnostic testing). ImprintSeq was highly sensitive for detecting MLIDs and enabled diagnostic criteria for MLID to be proposed. In a child with extreme MLID profile a probable genetic cause was identified.ConclusionImprintSeq provides a novel assay for clinical diagnostic and research studies of CIDs, MLIDs, and the role of disordered imprinting in human disease states.