BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :Set2-mediated histone methylation at H3K36 regulates diverse activities, including DNA repair, mRNA splicing, and suppression of inappropriate (cryptic) transcription. Although failure of Set2 to suppress cryptic transcription has been linked to decreased lifespan, the extent to which cryptic transcription influences other cellular functions is poorly understood. Here, we uncover a role for H3K36 methylation in the regulation of the nutrient stress response pathway. We found that the transcriptional response to nutrient stress was dysregulated in SET2-deleted (set2Δ) cells and was correlated with genome-wide bi-directional cryptic transcription that originated from within gene bodies. Antisense transcripts arising from these cryptic events extended into the promoters of the genes from which they arose and were associated with decreased sense transcription under nutrient stress conditions. These results suggest that Set2-enforced transcriptional fidelity is critical to the proper regulation of inducible and highly regulated transcription programs.

背景与目标： : H3K36的Set2-mediated组蛋白甲基化调节多种活动，包括DNA修复，mRNA剪接和抑制不适当的 (隐性) 转录。尽管Set2无法抑制隐性转录与寿命缩短有关，但对隐性转录影响其他细胞功能的程度知之甚少。在这里，我们揭示了H3K36甲基化在营养应激反应途径调节中的作用。我们发现，对营养应激的转录反应在SET2-deleted (set2Δ) 细胞中失调，并且与源自基因体内的全基因组双向隐秘转录相关。这些隐秘事件产生的反义转录本延伸到它们产生的基因的启动子中，并且在营养胁迫条件下与有义转录减少有关。这些结果表明，Set2-enforced的转录保真度对于适当调节可诱导和高度调节的转录程序至关重要。

BACKGROUND & AIMS: :Deregulated epigenetic mechanisms are likely involved in the pathogenesis of myelodysplastic syndromes (MDSs). Which genes are silenced by aberrant promotor methylation during MDS hematopoiesis has not been equivalently investigated. Using an in vitro differentiation model of human hematopoiesis, we generated defined differentiation stages (day 0, day 4, day 7, day 11) of erythro-, thrombo- and granulopoiesis from 13 MDS patients and seven healthy donors. Promotor methylation analysis of key regulatory genes involved in cell cycle control (p14, p15, p16, CHK2), DNA repair (hMLH1), apoptosis (p73, survivin, DAPK), and differentiation (RARb, WT1) was performed by methylation-specific polymerase chain reaction. Corresponding gene expression was analyzed by microarray (Affymetrix, HG-U133A). We provide evidence that p16, survivin, CHK2, and WT1 are affected by promotor hypermethylation in MDSs displaying a selective International Prognostic Scoring System risk association. A methylation-associated mRNA downregulation for specific hematopoietic lineages and differentiation stages is demonstrated for survivin, CHK2, and WT1. We identified a suppressed survivin mRNA expression in methylated samples during erythropoiesis, whereas WT1 and CHK2 methylation-related reduction of mRNA expression was found during granulopoiesis in all MDS risk types. Our data suggest that lineage-specific methylation-associated gene silencing of survivin, CHK2, and WT1 in MDS hematopoietic precursor cells may contribute to the MDS-specific phenotype

背景与目标： : 失调的表观遗传机制可能与骨髓增生异常综合征 (MDSs) 的发病机理有关。尚未对MDS造血过程中异常启动子甲基化使哪些基因沉默。使用人造血的体外分化模型，我们从13名MDS患者和7名健康供体中生成了明确的分化阶段 (第0天，第4天，第7天，第11天) 的红细胞生成，血栓生成和颗粒生成。通过甲基化特异性聚合酶链反应对参与细胞周期控制 (p14，p15，p16，CHK2)，DNA修复 (hMLH1)，凋亡 (p73，survivin，DAPK) 和分化 (RARb，WT1) 的关键调控基因进行启动子甲基化分析。通过微阵列 (Affymetrix，HG-U133A) 分析相应的基因表达。我们提供的证据表明，在显示选择性国际预后评分系统风险关联的MDSs中，p16，survivin，CHK2和WT1受到启动子高甲基化的影响。survivin，CHK2和wt1证明了特定造血谱系和分化阶段的甲基化相关mRNA下调。我们在红细胞生成过程中发现甲基化样品中survivin mRNA表达受到抑制，而在所有MDS风险类型中，在颗粒生成过程中发现WT1和CHK2甲基化相关的mRNA表达降低。我们的数据表明，MDS造血前体细胞中survivin，CHK2和WT1的谱系特异性甲基化相关基因沉默可能有助于MDS特异性表型

BACKGROUND & AIMS: PURPOSE:Glioblastoma is a universally fatal cancer of the central nervous system which responds poorly to treatment. MGMT has potential as a predictive biomarker in glioblastoma patients to determine treatment response. However, methods of measuring MGMT are currently unsatisfactory, and as such, use of this marker has not translated well into the clinic. This paper aims to review current methodology of MGMT measurement, with a focus on immunohistochemistry as a potential way forward. TOPICS AND METHODS: Studies of glioma patients where MGMT immunohistochemistry was undertaken, as well as the literature surrounding methylation analyses and the regulation of MGMT, were reviewed. RESULTS:All methods of measuring MGMT were disputed in some way in the literature. A trend of discordance between methylation analyses and protein analyses was present. There is a lack of standardisation in the measurement of MGMT, and as a result, it seems that there are highly variable results. CONCLUSIONS:No single method of MGMT analysis has emerged as a clear choice for routine clinical testing of MGMT in glioma patients. Although methylation analyses are favoured, their expense and inaccessibility are barriers to their use in routine clinical practice. More research into immunohistochemistry is needed to determine whether it can serve as a reliable and cost-effective alternative to methylation analyses.

背景与目标：

BACKGROUND & AIMS: :Aim: To investigate the associations between LINE1 methylation, an indicator for genome-wide hypomethylation, molecular and clinicopathological characteristics of gastric cancer (GC) patients. Patients & methods:LINE1 methylation statuses were examined in paired cancerous, non-neoplastic mucosa from 217 GC and gastric mucosa from separate group of 224 noncancer patients. CpG island methylator phenotype, TP53 and KRAS mutation, MLH1 methylation status and promoter hypermethylation of GC related and H. pylori-related genes were examined. Results: Lower LINE1 methylation was observed in primary GC compared with non-neoplastic gastric mucosa and associated with CpG island methylator phenotype, TP53 mutation, MLH1 methylation and promoter hypermethylation of GC related and H. pylori-related genes. Conclusion: Lower LINE1 methylation correlates specific molecular subtypes and promoter hypermethylation in GC.

背景与目标： 目的: 探讨全基因组低甲基化指标LINE1甲基化与胃癌 (GC) 患者的分子和临床病理特征之间的关系。患者和方法: 在来自217 GC的配对癌，非肿瘤性粘膜和来自224非癌患者的单独组的胃粘膜中检查LINE1甲基化状态。检测了CpG岛甲基化因子表型，TP53和KRAS突变，MLH1甲基化状态以及GC相关和H. pylori相关基因的启动子高甲基化。结果: 与非肿瘤性胃粘膜相比，原发性GC中存在较低的LINE1甲基化，并与CpG岛甲基化表型，TP53突变，MLH1甲基化以及GC相关和H. pylori相关基因的启动子高甲基化有关。结论: 下层1甲基化与GC中特定分子亚型和启动子高甲基化相关。

BACKGROUND & AIMS: In female mammalian cells, inactivation of one of the X chromosomes compensates the increased dosage of X-linked genes as compared with their male counterparts. This process is initiated by the X-inactive specific transcripts of the xist/XIST gene in cis, resulting in methylation of specific sites of genes to be silenced. However, in male germ cells, X inactivation is established by xist/XIST expression only. We investigated the X inactivation pattern in human testicular tumors of different histogenesis by analysis of XIST expression and methylation of the androgen receptor gene. XIST was expressed only in tumors derived from the germ cell lineage with supernumerical X chromosomesseminomas, nonseminomas, and spermatocytic seminomas. Although low expression was present in testicular parenchyma with spermatogenesis, XIST was expressed at a higher level in parenchyma with carcinoma in situ, the precursor lesion of seminomas and nonseminomas. Despite the consistent expression of XIST in germ-cell-derived tumors with gain of X chromosomes, methylation of the androgen receptor gene was present in all differentiated but only in a proportion of the undifferentiated nonseminomas. This differential pattern of methylation was also found in a number of representative cell lines. Our data indicate that the counting mechanism resulting in X inactivation is functional in testicular cancers of different histogenesis. Moreover, the differentiation-dependent pattern of X inactivation as reported during normal development in the case of multiple X chromosomes by methylation is retained in these tumors. We conclude therefore that X inactivation allows the excessive gain of X chromosomes found in germ-cell-derived tumors of the adult testis. In addition, this offers an interesting model to study the fundamental mechanisms of these processes.

背景与目标： 在雌性哺乳动物细胞中，与雄性对应物相比，X染色体之一的失活补偿了X连锁基因剂量的增加。此过程由cis中xist/XIST基因的X失活特异性转录本启动，导致待沉默基因的特定位点甲基化。然而，在雄性生殖细胞中，X失活仅通过xist/XIST表达建立。我们通过分析XIST表达和雄激素受体基因的甲基化，研究了不同组织发生的人睾丸肿瘤中的X失活模式。XIST仅在源自生殖细胞谱系的肿瘤中表达，这些肿瘤具有超数字X染色体精原细胞瘤，非精原细胞瘤和精细胞精原细胞瘤。尽管在精子发生的睾丸实质中存在低表达，但XIST在原位癌，精原细胞瘤和非精原细胞瘤的前体病变的实质中表达较高。尽管XIST在获得X染色体的生殖细胞衍生的肿瘤中一致表达，但在所有分化的非精原细胞瘤中，雄激素受体基因的甲基化都存在，但仅在未分化的非精原细胞瘤中。在许多代表性细胞系中也发现了这种甲基化的差异模式。我们的数据表明，导致X失活的计数机制在不同组织发生的睾丸癌中起作用。此外，在这些肿瘤中保留了在正常发育过程中通过甲基化引起的多个X染色体的X失活的分化依赖性模式。因此，我们得出结论，X失活允许在成年睾丸的生殖细胞衍生肿瘤中发现的X染色体的过度增加。此外，这提供了一个有趣的模型来研究这些过程的基本机制。

BACKGROUND & AIMS: :Analysis of circulating nucleic acids in bodily fluids, referred to as "liquid biopsies", is rapidly gaining prominence. Studies have shown that cell-free DNA (cfDNA) has great potential in characterizing tumor status and heterogeneity, as well as the response to therapy and tumor recurrence. DNA methylation is an epigenetic modification that plays an important role in a broad range of biological processes and diseases. It is well known that aberrant DNA methylation is generalizable across various samples and occurs early during the pathogenesis of cancer. Methylation patterns of cfDNA are also consistent with their originated cells or tissues. Systemic analysis of cfDNA methylation profiles has emerged as a promising approach for cancer detection and origin determination. In this review, we will summarize the technologies for DNA methylation analysis and discuss their feasibility for liquid biopsy applications. We will also provide a brief overview of the bioinformatic approaches for analysis of DNA methylation sequencing data. Overall, this review provides informative guidance for the selection of experimental and computational methods in cfDNA methylation-based studies.

背景与目标： : 体液中循环核酸的分析，被称为 “液体活检”，正在迅速得到重视。研究表明，无细胞DNA (cfDNA) 在表征肿瘤状态和异质性以及对治疗和肿瘤复发的反应方面具有巨大潜力。DNA甲基化是一种表观遗传修饰，在广泛的生物学过程和疾病中起着重要作用。众所周知，异常的DNA甲基化可在各种样品中推广，并且在癌症发病机理的早期发生。cfDNA的甲基化模式也与其起源的细胞或组织一致。cfDNA甲基化谱的系统分析已成为癌症检测和起源确定的有前途的方法。在这篇综述中，我们将总结用于DNA甲基化分析的技术，并讨论其在液体活检应用中的可行性。我们还将简要概述用于分析DNA甲基化测序数据的生物信息学方法。总体而言，这篇综述为基于cfDNA甲基化的研究中实验和计算方法的选择提供了有益的指导。

BACKGROUND & AIMS: :Triple-negative breast cancer (TNBC) has poor clinical prognosis. Lack of TNBC-specific biomarkers prevents active clinical intervention. We reasoned that TNBC must have its specific signature due to the lack of three key receptors to distinguish TNBC from other types of breast cancer. We also reasoned that coupling methylation and gene expression as a single unit may increase the specificity for the detected TNBC signatures. We further reasoned that choosing the proper controls may be critical to increasing the sensitivity to identify TNBC-specific signatures. Furthermore, we also considered that specific drugs could target the detected TNBC-specific signatures. We developed a system to identify potential TNBC signatures. It consisted of (1) coupling methylation and expression changes in TNBC to identify the methylation-regulated signature genes for TNBC; (2) using TPBC (triple-positive breast cancer) as the control to detect TNBC-specific signature genes; (3) searching in the drug database to identify those targeting TNBC signature genes. Using this system, we identified 114 genes with both altered methylation and expression, and 356 existing drugs targeting 10 of the 114 genes. Through docking and molecular dynamics simulation, we determined the structural basis between sapropterin, a drug used in the treatment of tetrahydrobiopterin deficiency, and PTGS2, a TNBC signature gene involved in the conversion of arachidonic acid to prostaglandins. Our study reveals the existence of rich TNBC-specific signatures, and many can be drug target and biomarker candidates for clinical applications.

背景与目标： : 三阴性乳腺癌 (TNBC) 临床预后较差。TNBC特异性生物标志物的缺乏阻碍了积极的临床干预。我们认为，由于缺乏三种关键受体来区分TNBC与其他类型的乳腺癌，TNBC必须具有其特定的特征。我们还认为，将甲基化和基因表达作为单个单元偶联可能会增加检测到的TNBC签名的特异性。我们进一步认为，选择适当的控件对于提高识别TNBC特定签名的敏感性可能至关重要。此外，我们还认为特定药物可以针对检测到的TNBC特异性特征。我们开发了一个识别潜在TNBC签名的系统。它由 (1) 结合甲基化和TNBC中的表达变化来鉴定TNBC的甲基化调节签名基因; (2) 以TPBC (三阳性乳腺癌) 为对照来检测TNBC特异性签名基因; (3) 在药物数据库中搜索以识别那些靶向TNBC签名基因。使用该系统，我们鉴定了114个具有改变的甲基化和表达的基因，并356了靶向10个114基因的现有药物。通过对接和分子动力学模拟，我们确定了用于治疗四氢生物蝶呤缺乏症的药物沙丙蝶呤与参与花生四烯酸向前列腺素转化的TNBC签名基因PTGS2之间的结构基础。我们的研究揭示了存在丰富的TNBC特异性签名，并且许多可能是临床应用的药物靶标和生物标志物候选者。

BACKGROUND & AIMS: :Bullying among children is ubiquitous and associated with pervasive mental health problems. However, little is known about the biological pathways that change after exposure to bullying. Epigenome-wide changes in DNA methylation in peripheral blood were studied from pre- to post measurement of bullying exposure, in a longitudinal study of the population-based Generation R Study and Avon Longitudinal Study of Parents and Children (combined n = 1,352). Linear mixed-model results were meta-analysed to estimate how DNA methylation changed as a function of exposure to bullying. Sensitivity analyses including co-occurring child characteristics and risks were performed, as well as a Gene Ontology analysis. A candidate follow-up was employed for CpG (cytosine-phosphate-guanine) sites annotated to 5-HTT and NR3C1. One site, cg17312179, showed small changes in DNA methylation associated to bullying exposure (b = -2.67e-03, SE = 4.97e-04, p = 7.17e-08). This site is annotated to RAB14, an oncogene related to Golgi apparatus functioning, and its methylation levels decreased for exposed but increased for non-exposed. This result was consistent across sensitivity analyses. Enriched Gene Ontology pathways for differentially methylated sites included cardiac function and neurodevelopmental processes. Top CpG sites tended to have overall low levels of DNA methylation, decreasing in exposed, increasing in non-exposed individuals. There were no gene-wide corrected findings for 5-HTT and NR3C1. This is the first study to identify changes in DNA methylation associated with bullying exposure at the epigenome-wide significance level. Consistent with other population-based studies, we do not find evidence for strong associations between bullying exposure and DNA methylation.

背景与目标： : 儿童欺凌无处不在，并与普遍存在的精神卫生问题相关。然而，人们对暴露于欺凌之后发生变化的生物途径知之甚少。在基于人群的R世代研究和父母和儿童的Avon纵向研究的纵向研究中，从欺凌暴露的测量前后研究了外周血中DNA甲基化的表观基因组范围变化 (合并n = 1,352)。对线性混合模型结果进行了荟萃分析，以估计DNA甲基化如何随暴露于欺凌行为而变化。进行了敏感性分析，包括共同发生的儿童特征和风险，以及基因本体论分析。对5-HTT和NR3C1注释的CpG (胞嘧啶-磷酸-鸟嘌呤) 位点进行了候选随访。一个位点cg17312179显示出与欺凌暴露相关的DNA甲基化的微小变化 (b = -2.67e-03，SE = 4.97e-04，p = 7.17e-08)。该位点与RAB14注释，RAB14是一种与高尔基体功能有关的癌基因，其甲基化水平在暴露时降低，而在未暴露时升高。该结果在敏感性分析中是一致的。差异甲基化位点的丰富基因本体论途径包括心脏功能和神经发育过程。顶级CpG位点的DNA甲基化水平总体较低，暴露时降低，未暴露个体中增加。5-HTT和NR3C1没有全基因校正的发现。这是第一项在表观基因组范围的显着性水平上确定与欺凌暴露相关的DNA甲基化变化的研究。与其他基于人群的研究一致，我们没有发现欺凌暴露与DNA甲基化之间强烈关联的证据。

BACKGROUND & AIMS: :The DNA damage response is mediated by both DNA repair proteins and epigenetic markers. Here, we observe that N6-methyladenosine (m6A), a mark of the epitranscriptome, was common in RNAs accumulated at UV-damaged chromatin; however, inhibitors of RNA polymerases I and II did not affect the m6A RNA level at the irradiated genomic regions. After genome injury, m6A RNAs either diffused to the damaged chromatin or appeared at the lesions enzymatically. DNA damage did not change the levels of METTL3 and METTL14 methyltransferases. In a subset of irradiated cells, only the METTL16 enzyme, responsible for m6A in non-coding RNAs as well as for splicing regulation, was recruited to microirradiated sites. Importantly, the levels of the studied splicing factors were not changed by UVA light. Overall, if the appearance of m6A RNAs at DNA lesions is regulated enzymatically, this process must be mediated via the coregulatory function of METTL-like enzymes. This event is additionally accompanied by radiation-induced depletion of 2,2,7-methylguanosine (m3G/TMG) in RNA. Moreover, UV-irradiation also decreases the global cellular level of N1-methyladenosine (m1A) in RNAs. Based on these results, we prefer a model in which m6A RNAs rapidly respond to radiation-induced stress and diffuse to the damaged sites. The level of both (m1A) RNAs and m3G/TMG in RNAs is reduced as a consequence of DNA damage, recognized by the nucleotide excision repair mechanism.

背景与目标： : DNA损伤反应是由DNA修复蛋白和表观遗传标记介导的。在这里，我们观察到N6-methyladenosine (m6A) 是表位组的标志，在紫外线受损的染色质处积累的RNA中很常见; 然而，RNA聚合酶I和II的抑制剂不影响辐照基因组区域的m6A RNA水平。基因组损伤后，m6A rna扩散到受损的染色质中或以酶促的方式出现在病变处。DNA损伤不会改变METTL3和METTL14甲基转移酶的水平。在受照射的细胞的子集中，只有负责非编码rna中的m6A以及剪接调节的METTL16酶被募集到微照射位点。重要的是，所研究的拼接因子的水平不会因UVA光而改变。总体而言，如果通过酶调节DNA损伤处m6A rna的出现，则该过程必须通过METTL样酶的共调节功能来介导。该事件还伴随着辐射诱导的RNA中2,2，7-甲基鸟苷 (m3G/TMG) 的耗尽。此外，紫外线照射还降低了rna中N1-methyladenosine (m1A) 的整体细胞水平。基于这些结果，我们更喜欢m6A rna快速响应辐射诱导的压力并扩散到受损部位的模型。由于DNA损伤，rna中 (m1A) rna和m3G/TMG的水平均降低，这被核苷酸切除修复机制所识别。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :Krüppel-like factor 4 (KLF4) has a tumor suppressor role in the progression of gastric cancer (GC), and inhibition or loss of KLF4 expression was identified in GC. The aim of this study was to explore the new molecular mechanism of KLF4 inactivation in gastric cancer. Herein, we report that Helicobacter pylori infection or Cag pathogenicity island protein A (CagA) gene transduction resulted in KLF4 expression downregulation and promoted gastric epithelial cell and gastric cancel cell proliferation, migration, and colony formation. Mechanistically, we found that CagA gene transduction led to DNA methylation of the KLF4 promoter, an effect that was relevant to the significant downregulation of TET1 expression. Causally, knockdown of TET1 expression decreased KLF4 expression, whereas overexpression of TET1 had the opposite effect. Clinically, we found that KLF4 expression and the 5-hmC levels were lower in GC cells with H pylori infection than in GC cells without H pylori infection. Thus, our study not only sheds new light on how H pylori infection promotes the progression of GC but also elucidates a novel mechanism of KLF4 inactivation in GC pathogenesis. During pathogenesis, an alteration in the H pylori/CagA-TET1-KLF4 signaling pathway plays a critical role, suggesting that this pathway may be a prospective target for gastric carcinoma intervention and therapy.

背景与目标： : kr ü ppel样因子4 (KLF4) 在胃癌 (GC) 的进展中具有抑癌作用，并且在GC中鉴定出KLF4表达的抑制或丧失。本研究旨在探讨KLF4在胃癌中失活的分子机制。本文报道幽门螺杆菌感染或Cag致病性岛蛋白A (CagA) 基因转导导致KLF4表达下调，促进胃上皮细胞和胃取消细胞增殖、迁移和集落形成。从机制上讲，我们发现CagA基因转导导致KLF4启动子的DNA甲基化，这与TET1表达的显着下调有关。原因是，敲除TET1表达会降低KLF4表达，而TET1的过表达则具有相反的作用。临床上，我们发现幽门螺杆菌感染的GC细胞中KLF4表达和5-hmC水平低于不幽门螺杆菌感染的GC细胞。因此，我们的研究不仅为幽门螺杆菌感染如何促进GC的进展提供了新的思路，而且还阐明了GC发病机理中KLF4失活的新机制。在发病过程中，幽门螺杆菌/CagA-TET1-KLF4信号通路的改变起着至关重要的作用，表明该通路可能是胃癌干预和治疗的前瞻性靶标。

BACKGROUND & AIMS: :DNA methylation is an ancient process found in all domains of life. Although the enzymes that mediate methylation have remained highly conserved, DNA methylation has been adapted for a variety of uses throughout evolution, including defense against transposable elements and control of gene expression. Defects in DNA methylation are linked to human diseases, including cancer. Methylation has been lost several times in the course of animal and fungal evolution, thus limiting the opportunity for study in common model organisms. In the past decade, plants have emerged as a premier model system for genetic dissection of DNA methylation. A recent combination of plant genetics with powerful genomic approaches has led to a number of exciting discoveries and promises many more.

背景与目标： : DNA甲基化是一个古老的过程，存在于生命的所有领域。尽管介导甲基化的酶保持高度保守，但DNA甲基化已适用于整个进化过程中的多种用途，包括防御转座因子和控制基因表达。DNA甲基化缺陷与人类疾病有关，包括癌症。在动物和真菌进化过程中，甲基化已多次丢失，从而限制了在常见模式生物中进行研究的机会。在过去的十年中，植物已成为DNA甲基化基因解剖的主要模型系统。最近将植物遗传学与强大的基因组方法相结合，导致了许多令人兴奋的发现，并有望实现更多。

BACKGROUND & AIMS: BACKGROUND:Coeliac disease (CD) is a autoimmune disease characterised by mucosal inflammation in the small intestine in response to dietary gluten. Genetic factors play a key role with CD individuals carrying either the HLA-DQ2 or HLA-DQ8 haplotype, however these haplotypes are present in half the general population making them necessary but insufficient to cause CD. Epigenetic modifications, including DNA methylation that can change in response to environmental exposure could help to explain how interactions between genes and environmental factors combine to trigger disease development. Identifying changes in DNA methylation profiles in individuals with CD could help discover novel genomic regions involved in the onset and development of CD. METHODS:The Illumina InfiniumMethylation450 Beadchip array (HM450) was used to compare DNA methylation profiles in saliva, in CD and non-CD affected individuals. CD individuals who had been diagnosed at least 2 years previously; were on a GFD; and who were currently asymptomatic; were compared to age and sex-matched non-CD affected healthy controls. Bisulphite pyrosequencing was used to validate regions found to be differentially methylated. These regions were also validated in a second larger cohort of CD and non-CD affected individuals. RESULTS:Methylation differences within the HLA region at HLA-DQB1 were identified on HM450 but could not be confirmed with pyrosequencing. Significant methylation differences near the SLC17A3 gene were confirmed on pyrosequencing in the initial pilot cohort. Interestingly pyrosequencing sequencing of these same sites within a second cohort of CD and non-CD affected controls produced significant methylation differences in the opposite direction. CONCLUSION:Altered DNA methylation profiles appear to be present in saliva in CD individuals. Further work to confirm whether these differences are truly associated with CD is needed.

背景与目标：

BACKGROUND & AIMS: :Major depressive disorder (MDD) is the leading cause of disability worldwide and is associated with high rates of suicide and medical comorbidities. Current antidepressant medications are suboptimal, as most MDD patients fail to achieve complete remission from symptoms. At present, clinicians are unable to predict which antidepressant is most effective for a particular patient, exposing patients to multiple medication trials and side effects. Since MDD's etiology includes interactions between genes and environment, the epigenome is of interest for predictive utility and treatment monitoring. Epigenetic mechanisms of antidepressant medications are incompletely understood. Differences in epigenetic profiles may impact treatment response. A systematic literature search yielded 24 studies reporting the interaction between antidepressants and eight genes (BDNF, MAOA, SLC6A2, SLC6A4, HTR1A, HTR1B, IL6, IL11) and whole genome methylation. Methylation of certain sites within BDNF, SLC6A4, HTR1A, HTR1B, IL11, and the whole genome was predictive of antidepressant response. Comparing DNA methylation in patients during depressive episodes, during treatment, in remission, and after antidepressant cessation would help clarify the influence of antidepressant medications on DNA methylation. Individuals' unique methylation profiles may be used clinically for personalization of antidepressant choice in the future.

背景与目标： : 重度抑郁症 (MDD) 是全球残疾的主要原因，与自杀和医疗合并症的高发生率有关。当前的抗抑郁药物是次优的，因为大多数MDD患者无法完全缓解症状。目前，临床医生无法预测哪种抗抑郁药对特定患者最有效，使患者暴露于多种药物试验和副作用。由于MDD的病因包括基因与环境之间的相互作用，因此表观基因组对于预测效用和治疗监测很有意义。抗抑郁药物的表观遗传机制尚不完全清楚。表观遗传谱的差异可能会影响治疗反应。系统的文献搜索产生了24项研究，报告了抗抑郁药与八个基因 (BDNF，MAOA，SLC6A2，SLC6A4，HTR1A，HTR1B，IL6，IL11) 和全基因组甲基化之间的相互作用。BDNF，SLC6A4，HTR1A，HTR1B，IL11和全基因组中某些位点的甲基化可预测抗抑郁反应。在抑郁发作期间，治疗期间，缓解期间以及抗抑郁药停止后比较患者的DNA甲基化将有助于阐明抗抑郁药物对DNA甲基化的影响。个人独特的甲基化谱可以在临床上用于抗抑郁药的个性化选择。