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CRISPR/dCAS9-mediated DNA demethylation screen identifies functional epigenetic determinants of colorectal cancer. CRISPR/dCAS9介导的DNA去甲基化筛选鉴定癌症的功能性表观遗传决定簇。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-24 DOI: 10.1186/s13148-023-01546-1
Juan Ramón Tejedor, Alfonso Peñarroya, Javier Gancedo-Verdejo, Pablo Santamarina-Ojeda, Raúl F Pérez, Sara López-Tamargo, Ana Díez-Borge, Juan J Alba-Linares, Nerea González-Del-Rey, Rocío G Urdinguio, Cristina Mangas, Annalisa Roberti, Virginia López, Teresa Morales-Ruiz, Rafael R Ariza, Teresa Roldán-Arjona, Mónica Meijón, Luis Valledor, María Jesús Cañal, Daniel Fernández-Martínez, María Fernández-Hevia, Paula Jiménez-Fonseca, Luis J García-Flórez, Agustín F Fernández, Mario F Fraga

Background: Promoter hypermethylation of tumour suppressor genes is frequently observed during the malignant transformation of colorectal cancer (CRC). However, whether this epigenetic mechanism is functional in cancer or is a mere consequence of the carcinogenic process remains to be elucidated.

Results: In this work, we performed an integrative multi-omic approach to identify gene candidates with strong correlations between DNA methylation and gene expression in human CRC samples and a set of 8 colon cancer cell lines. As a proof of concept, we combined recent CRISPR-Cas9 epigenome editing tools (dCas9-TET1, dCas9-TET-IM) with a customized arrayed gRNA library to modulate the DNA methylation status of 56 promoters previously linked with strong epigenetic repression in CRC, and we monitored the potential functional consequences of this DNA methylation loss by means of a high-content cell proliferation screen. Overall, the epigenetic modulation of most of these DNA methylated regions had a mild impact on the reactivation of gene expression and on the viability of cancer cells. Interestingly, we found that epigenetic reactivation of RSPO2 in the tumour context was associated with a significant impairment in cell proliferation in p53-/- cancer cell lines, and further validation with human samples demonstrated that the epigenetic silencing of RSPO2 is a mid-late event in the adenoma to carcinoma sequence.

Conclusions: These results highlight the potential role of DNA methylation as a driver mechanism of CRC and paves the way for the identification of novel therapeutic windows based on the epigenetic reactivation of certain tumour suppressor genes.

背景:在癌症恶性转化过程中,肿瘤抑制基因的启动子高甲基化是常见的。然而,这种表观遗传机制在癌症中是否起作用,或者仅仅是致癌过程的结果,还有待阐明。结果:在这项工作中,我们采用了一种综合的多组学方法来识别人类CRC样本和一组8个结肠癌癌症细胞系中DNA甲基化与基因表达之间具有强相关性的候选基因。作为概念验证,我们将最近的CRISPR-Cas9表观基因组编辑工具(dCas9-TET1,dCas9-TET-IM)与定制的阵列gRNA文库相结合,以调节先前与CRC中的强表观遗传抑制相关的56个启动子的DNA甲基化状态,并通过高含量细胞增殖筛查监测这种DNA甲基化缺失的潜在功能后果。总体而言,这些DNA甲基化区域中的大多数的表观遗传调节对基因表达的重新激活和癌症细胞的生存能力有轻微影响。有趣的是,我们发现肿瘤背景下RSPO2的表观遗传再激活与p53-/-neneneba癌症细胞系中细胞增殖的显著损伤相关,并且对人类样本的进一步验证表明,RSPO2表观遗传沉默是腺瘤-癌序列中的中晚期事件。结论:这些结果突出了DNA甲基化作为CRC驱动机制的潜在作用,并为基于某些肿瘤抑制基因的表观遗传学再激活识别新的治疗窗口铺平了道路。
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引用次数: 0
Association between acetaminophen metabolites and CYP2E1 DNA methylation level in neonate cord blood in the Boston Birth Cohort. 波士顿出生队列新生儿脐血中对乙酰氨基酚代谢产物与CYP2E1 DNA甲基化水平的相关性。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-18 DOI: 10.1186/s13148-023-01551-4
Yijun Li, Xiumei Hong, Liming Liang, Xiaobin Wang, Christine Ladd-Acosta

Background: Acetaminophen is a commonly used medication by pregnant women and is known to cross the placenta. However, little is known about the biological mechanisms that regulate acetaminophen in the developing offspring. Cytochrome 2E1 (CYP2E1) is the primary enzyme responsible for the conversion of acetaminophen to its toxic metabolite. Ex vivo studies have shown that the CYP2E1 gene expression in human fetal liver and placenta is largely controlled by DNA methylation (DNAm) at CpG sites located in the gene body of CYP2E1 at the 5' end. To date, no population studies have examined the association between acetaminophen metabolite and fetal DNAm of CYP2E1 at birth.

Methods: We utilized data from the Boston Birth Cohort (BBC) which represents an urban, low-income, racially and ethnically diverse population in Boston, Massachusetts. Acetaminophen metabolites were measured in the cord plasma of newborns enrolled in BBC between 2003 and 2013 using liquid chromatography-tandem mass spectrometry. DNAm at 28 CpG sites of CYP2E1 was measured by Illumina Infinium MethylationEPIC BeadChip. We used linear regression to identify differentially methylated CpG sites and the "DiffVar" method to identify differences in methylation variation associated with the detection of acetaminophen, adjusting for cell heterogeneity and batch effects. The false discovery rate (FDR) was calculated to account for multiple comparisons.

Results: Among the 570 newborns included in this study, 96 (17%) had detectable acetaminophen in cord plasma. We identified 7 differentially methylated CpGs (FDR < 0.05) associated with the detection of acetaminophen and additional 4 CpGs showing a difference in the variation of methylation (FDR < 0.05). These CpGs were all located in the gene body of CYP2E1 at the 5' end and had a 3-6% lower average methylation level among participants with detectable acetaminophen compared to participants without. The CpG sites we identified overlap with previously identified DNase hypersensitivity and open chromatin regions in the ENCODE project, suggesting potential regulatory functions.

Conclusions: In a US birth cohort, we found detection of cord biomarkers of acetaminophen was associated with DNAm level of CYP2E1 in cord blood. Our findings suggest that DNA methylation of CYP2E1 may be an important regulator of acetaminophen levels in newborns.

背景:对乙酰氨基酚是孕妇常用的药物,已知会穿过胎盘。然而,对发育中的后代中调节对乙酰氨基酚的生物学机制知之甚少。细胞色素2E1(CYP2E1)是负责将对乙酰氨基酚转化为其毒性代谢产物的主要酶。体外研究表明,CYP2E1基因在人类胎儿肝脏和胎盘中的表达在很大程度上受CYP2E1 5’端基因体CpG位点的DNA甲基化(DNAm)控制。到目前为止,还没有群体研究检测对乙酰氨基酚代谢产物与出生时CYP2E1的胎儿DNAm之间的关系。方法:我们使用了波士顿出生队列(BBC)的数据,该队列代表了马萨诸塞州波士顿的城市、低收入、种族和民族多样性人群。2003年至2013年间,使用液相色谱-串联质谱法对英国广播公司登记的新生儿脐带血浆中的对乙酰氨基酚代谢物进行了测量。通过Illumina Infinium MethylationEPIC BeadChip测量CYP2E1 28个CpG位点的DNAm。我们使用线性回归来识别差异甲基化的CpG位点,并使用“DiffVar”方法来识别与检测对乙酰氨基酚相关的甲基化变化的差异,调整细胞异质性和批次效应。计算错误发现率(FDR)是为了考虑多次比较。结果:在纳入本研究的570名新生儿中,96名(17%)的脐带血浆中检测到对乙酰氨基酚。我们鉴定了7个差异甲基化CpG(FDR 结论:在美国出生队列中,我们发现检测对乙酰氨基酚的脐带生物标志物与脐带血中CYP2E1的DNAm水平有关。我们的研究结果表明,CYP2E1的DNA甲基化可能是新生儿对乙酰氨基酚水平的重要调节因子。
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引用次数: 0
Cross-platform comparisons for targeted bisulfite sequencing of MGISEQ-2000 and NovaSeq6000. MGISEQ-2000和NovaSeq6000靶向亚硫酸盐测序的跨平台比较
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-14 DOI: 10.1186/s13148-023-01543-4
Jin Sun, Mingyang Su, Jianhua Ma, Minjie Xu, Chengcheng Ma, Wei Li, Rui Liu, Qiye He, Zhixi Su

Background: An accurate and reproducible next-generation sequencing platform is essential to identify malignancy-related abnormal DNA methylation changes and translate them into clinical applications including cancer detection, prognosis, and surveillance. However, high-quality DNA methylation sequencing has been challenging because poor sequence diversity of the bisulfite-converted libraries severely impairs sequencing quality and yield. In this study, we tested MGISEQ-2000 Sequencer's capability of DNA methylation sequencing with a published non-invasive pancreatic cancer detection assay, using NovaSeq6000 as the benchmark.

Results: We sequenced a series of synthetic cell-free DNA (cfDNA) samples with different tumor fractions and found MGISEQ-2000 yielded data with similar quality as NovaSeq6000. The methylation levels measured by MGISEQ-2000 demonstrated high consistency with NovaSeq6000. Moreover, MGISEQ-2000 showed a comparable analytic sensitivity with NovaSeq6000, suggesting its potential for clinical detection. As to evaluate the clinical performance of MGISEQ-2000, we sequenced 24 clinical samples and predicted the pathology of the samples with a clinical diagnosis model, PDACatch classifier. The clinical model performance of MGISEQ-2000's data was highly consistent with that of NovaSeq6000's data, with the area under the curve of 1. We also tested the model's robustness with MGISEQ-2000's data when reducing the sequencing depth. The results showed that MGISEQ-2000's data showed matching robustness of the PDACatch classifier with NovaSeq6000's data.

Conclusions: Taken together, MGISEQ-2000 demonstrated similar data quality, consistency of the methylation levels, comparable analytic sensitivity, and matching clinical performance, supporting its application in future non-invasive early cancer detection investigations by detecting distinct methylation patterns of cfDNAs.

背景:准确和可重复的下一代测序平台对于识别恶性肿瘤相关的异常DNA甲基化变化并将其转化为包括癌症检测、预后和监测在内的临床应用至关重要。然而,高质量的DNA甲基化测序一直具有挑战性,因为亚硫酸转化文库的序列多样性差严重影响了测序质量和产量。在本研究中,我们以NovaSeq6000为基准,用已发表的无创胰腺癌检测方法测试了MGISEQ-2000 Sequencer的DNA甲基化测序能力。结果:我们对一系列具有不同肿瘤组分的合成无细胞DNA (cfDNA)样本进行了测序,发现MGISEQ-2000获得的数据质量与NovaSeq6000相似。MGISEQ-2000测定的甲基化水平与NovaSeq6000高度一致。此外,MGISEQ-2000显示出与NovaSeq6000相当的分析灵敏度,表明其具有临床检测的潜力。为了评估MGISEQ-2000的临床性能,我们对24份临床样本进行了测序,并使用临床诊断模型PDACatch分类器预测了样本的病理。MGISEQ-2000数据的临床模型性能与NovaSeq6000数据高度一致,曲线下面积为1。我们还使用MGISEQ-2000的数据在降低测序深度时检验了模型的稳健性。结果表明,MGISEQ-2000的数据与NovaSeq6000的数据具有匹配的鲁棒性。结论:综上所述,MGISEQ-2000具有相似的数据质量、甲基化水平的一致性、可比较的分析灵敏度和匹配的临床性能,支持其通过检测不同的cfdna甲基化模式在未来非侵入性早期癌症检测研究中的应用。
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引用次数: 0
Globally elevated levels of histone H3 lysine 9 trimethylation in early infancy are associated with poor growth trajectory in Bangladeshi children. 全球范围内婴儿早期组蛋白H3赖氨酸9三甲基化水平升高与孟加拉国儿童生长轨迹不良有关。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-11 DOI: 10.1186/s13148-023-01548-z
Kristyna Kupkova, Savera J Shetty, Marilyn G Pray-Grant, Patrick A Grant, Rashidul Haque, William A Petri, David T Auble

Background: Stunting is a global health problem affecting hundreds of millions of children worldwide and contributing to 45% of deaths in children under the age of five. Current therapeutic interventions have limited efficacy. Understanding the epigenetic changes underlying stunting will elucidate molecular mechanisms and likely lead to new therapies.

Results: We profiled the repressive mark histone H3 lysine 9 trimethylation (H3K9me3) genome-wide in peripheral blood mononuclear cells (PBMCs) from 18-week-old infants (n = 15) and mothers (n = 14) enrolled in the PROVIDE study established in an urban slum in Bangladesh. We associated H3K9me3 levels within individual loci as well as genome-wide with anthropometric measurements and other biomarkers of stunting and performed functional annotation of differentially affected regions. Despite the relatively small number of samples from this vulnerable population, we observed globally elevated H3K9me3 levels were associated with poor linear growth between birth and one year of age. A large proportion of the differentially methylated genes code for proteins targeting viral mRNA and highly significant regions were enriched in transposon elements with potential regulatory roles in immune system activation and cytokine production. Maternal data show a similar trend with child's anthropometry; however, these trends lack statistical significance to infer an intergenerational relationship.

Conclusions: We speculate that high H3K9me3 levels may result in poor linear growth by repressing genes involved in immune system activation. Importantly, changes to H3K9me3 were detectable before the overt manifestation of stunting and therefore may be valuable as new biomarkers of stunting.

背景:发育迟缓是一个全球性的健康问题,影响着全世界数亿儿童,造成了45%的5岁以下儿童死亡。目前的治疗干预措施效果有限。了解发育迟缓背后的表观遗传变化将阐明分子机制,并可能导致新的治疗方法。结果:我们分析了18周大的婴儿(n = 15)和母亲(n = 14)外周血单个核细胞(PBMCs)中抑制标记组蛋白H3赖氨酸9三甲基化(H3K9me3)的全基因组图谱,这些婴儿(n = 15)和母亲(n = 14)参加了在孟加拉国城市贫民窟建立的提供研究。我们将个体基因座内的H3K9me3水平以及全基因组与人体测量和其他发育迟缓的生物标志物联系起来,并对差异影响区域进行了功能注释。尽管来自这一脆弱人群的样本数量相对较少,但我们观察到,全球范围内H3K9me3水平升高与出生至1岁之间的不良线性增长有关。大量编码病毒mRNA蛋白的差异甲基化基因和高度显著区域在转座子元件中富集,这些转座子元件在免疫系统激活和细胞因子产生中具有潜在的调节作用。母亲的数据与儿童的人体测量数据显示出类似的趋势;然而,这些趋势缺乏统计意义来推断代际关系。结论:我们推测高H3K9me3水平可能通过抑制参与免疫系统激活的基因导致线性生长不良。重要的是,H3K9me3的变化在发育迟缓的明显表现之前就被检测到,因此可能作为发育迟缓的新生物标志物而有价值。
{"title":"Globally elevated levels of histone H3 lysine 9 trimethylation in early infancy are associated with poor growth trajectory in Bangladeshi children.","authors":"Kristyna Kupkova, Savera J Shetty, Marilyn G Pray-Grant, Patrick A Grant, Rashidul Haque, William A Petri, David T Auble","doi":"10.1186/s13148-023-01548-z","DOIUrl":"10.1186/s13148-023-01548-z","url":null,"abstract":"<p><strong>Background: </strong>Stunting is a global health problem affecting hundreds of millions of children worldwide and contributing to 45% of deaths in children under the age of five. Current therapeutic interventions have limited efficacy. Understanding the epigenetic changes underlying stunting will elucidate molecular mechanisms and likely lead to new therapies.</p><p><strong>Results: </strong>We profiled the repressive mark histone H3 lysine 9 trimethylation (H3K9me3) genome-wide in peripheral blood mononuclear cells (PBMCs) from 18-week-old infants (n = 15) and mothers (n = 14) enrolled in the PROVIDE study established in an urban slum in Bangladesh. We associated H3K9me3 levels within individual loci as well as genome-wide with anthropometric measurements and other biomarkers of stunting and performed functional annotation of differentially affected regions. Despite the relatively small number of samples from this vulnerable population, we observed globally elevated H3K9me3 levels were associated with poor linear growth between birth and one year of age. A large proportion of the differentially methylated genes code for proteins targeting viral mRNA and highly significant regions were enriched in transposon elements with potential regulatory roles in immune system activation and cytokine production. Maternal data show a similar trend with child's anthropometry; however, these trends lack statistical significance to infer an intergenerational relationship.</p><p><strong>Conclusions: </strong>We speculate that high H3K9me3 levels may result in poor linear growth by repressing genes involved in immune system activation. Importantly, changes to H3K9me3 were detectable before the overt manifestation of stunting and therefore may be valuable as new biomarkers of stunting.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10422758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10102942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Introduction of a multiplex amplicon sequencing assay to quantify DNA methylation in target cytosine markers underlying four selected epigenetic clocks. 引入多重扩增子测序测定,以量化四种选择的表观遗传时钟下靶胞嘧啶标记的DNA甲基化。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-10 DOI: 10.1186/s13148-023-01545-2
Ewelina Pośpiech, Aleksandra Pisarek, Joanna Rudnicka, Rezvan Noroozi, Michał Boroń, Aleksander Masny, Bożena Wysocka, Kamila Migacz-Gruszka, Dagmara Lisman, Paulina Pruszkowska-Przybylska, Magdalena Kobus, Maria Szargut, Joanna Dowejko, Kamila Stanisz, Julia Zacharczuk, Piotr Zieliński, Aneta Sitek, Andrzej Ossowski, Magdalena Spólnicka, Wojciech Branicki

Background: DNA methylation analysis has proven to be a powerful tool for age assessment. However, the implementation of epigenetic age prediction in diagnostics or routine forensic casework requires appropriate laboratory methods. In this study, we aimed to compare the performance of large-scale DNA methylation analysis protocols that show promise in terms of accuracy, throughput, multiplexing capacity, and high sensitivity.

Results: The protocols were designed to target a predefined panel of 161 genomic CG/CA sites from four known estimators of epigenetic age-related parameters, optimized and validated using artificially methylated controls or blood samples. We successfully targeted 96% of these loci using two enrichment protocols: Ion AmpliSeq™, an amplicon-based method integrated with Ion Torrent S5, and SureSelectXT Methyl-Seq, a hybridization-based method followed by MiSeq FGx sequencing. Both protocols demonstrated high accuracy and robustness. Although hybridization assays have greater multiplexing capabilities, the best overall performance was observed for the amplicon-based protocol with the lowest variability in DNA methylation at 25 ng of starting DNA, mean observed marker coverage of ~ 6.7 k reads, and accuracy of methylation quantification with a mean absolute difference between observed and expected methylation beta value of 0.054. The Ion AmpliSeq method correlated strongly with genome-scale EPIC microarray data (R = 0.91) and showed superiority in terms of methylation measurement accuracy. Method-to-method bias was accounted for by the use of linear transformation, which provided a highly accurate prediction of calendar age with a mean absolute error of less than 5 years for the VISAGE and Hannum age clocks used. The pace of aging (PoAm) and the mortality risk score (MRS) estimators included in our panel represent next-generation clocks, were found to have low to moderate correlations with the VISAGE and Hannum models (R < 0.75), and thus may capture different aspects of epigenetic aging.

Conclusions: We propose a laboratory tool that allows the quantification of DNA methylation in cytosines underlying four different clocks, thus providing broad information on epigenetic aging while maintaining a reasonable number of CpG markers, opening the way to a wide range of applications in forensics, medicine, and healthcare.

背景:DNA甲基化分析已被证明是年龄评估的有力工具。然而,在诊断或常规法医案件工作中实施表观遗传年龄预测需要适当的实验室方法。在这项研究中,我们旨在比较大规模DNA甲基化分析方案的性能,这些方案在准确性、吞吐量、多路复用能力和高灵敏度方面表现出前景。结果:该方案旨在针对来自四个已知表观遗传年龄相关参数估计器的161个基因组CG/CA位点的预定义组,并使用人工甲基化对照或血液样本进行优化和验证。我们使用两种富集方案成功靶向了96%的这些基因座:Ion AmpliSeq™(一种基于扩增子的方法,与Ion Torrent S5集成)和SureSelectXT Methyl-Seq(一种基于杂交的方法,随后进行MiSeq FGx测序)。两种方案均具有较高的准确性和鲁棒性。尽管杂交分析具有更强的多路复制能力,但基于扩增子的方案的总体性能最好,在起始DNA 25 ng时,DNA甲基化的变异性最低,平均观察到的标记覆盖率为~ 6.7 k reads,甲基化量化的准确性,观察到的甲基化与预期的甲基化β值之间的平均绝对差为0.054。离子AmpliSeq方法与基因组尺度EPIC微阵列数据相关性强(R = 0.91),在甲基化测量精度方面具有优势。方法对方法的偏差是通过使用线性变换来解释的,线性变换为使用的VISAGE和Hannum年龄时钟提供了高度准确的日历年龄预测,平均绝对误差小于5年。我们小组中包括的衰老速度(PoAm)和死亡风险评分(MRS)估计值代表下一代时钟,被发现与VISAGE和Hannum模型具有低到中等的相关性(R结论:我们提出了一种实验室工具,可以量化四种不同时钟下胞嘧啶中的DNA甲基化,从而提供有关表观遗传衰老的广泛信息,同时保持合理数量的CpG标记,为法医、医学和医疗保健领域的广泛应用开辟道路。
{"title":"Introduction of a multiplex amplicon sequencing assay to quantify DNA methylation in target cytosine markers underlying four selected epigenetic clocks.","authors":"Ewelina Pośpiech, Aleksandra Pisarek, Joanna Rudnicka, Rezvan Noroozi, Michał Boroń, Aleksander Masny, Bożena Wysocka, Kamila Migacz-Gruszka, Dagmara Lisman, Paulina Pruszkowska-Przybylska, Magdalena Kobus, Maria Szargut, Joanna Dowejko, Kamila Stanisz, Julia Zacharczuk, Piotr Zieliński, Aneta Sitek, Andrzej Ossowski, Magdalena Spólnicka, Wojciech Branicki","doi":"10.1186/s13148-023-01545-2","DOIUrl":"10.1186/s13148-023-01545-2","url":null,"abstract":"<p><strong>Background: </strong>DNA methylation analysis has proven to be a powerful tool for age assessment. However, the implementation of epigenetic age prediction in diagnostics or routine forensic casework requires appropriate laboratory methods. In this study, we aimed to compare the performance of large-scale DNA methylation analysis protocols that show promise in terms of accuracy, throughput, multiplexing capacity, and high sensitivity.</p><p><strong>Results: </strong>The protocols were designed to target a predefined panel of 161 genomic CG/CA sites from four known estimators of epigenetic age-related parameters, optimized and validated using artificially methylated controls or blood samples. We successfully targeted 96% of these loci using two enrichment protocols: Ion AmpliSeq™, an amplicon-based method integrated with Ion Torrent S5, and SureSelect<sup>XT</sup> Methyl-Seq, a hybridization-based method followed by MiSeq FGx sequencing. Both protocols demonstrated high accuracy and robustness. Although hybridization assays have greater multiplexing capabilities, the best overall performance was observed for the amplicon-based protocol with the lowest variability in DNA methylation at 25 ng of starting DNA, mean observed marker coverage of ~ 6.7 k reads, and accuracy of methylation quantification with a mean absolute difference between observed and expected methylation beta value of 0.054. The Ion AmpliSeq method correlated strongly with genome-scale EPIC microarray data (R = 0.91) and showed superiority in terms of methylation measurement accuracy. Method-to-method bias was accounted for by the use of linear transformation, which provided a highly accurate prediction of calendar age with a mean absolute error of less than 5 years for the VISAGE and Hannum age clocks used. The pace of aging (PoAm) and the mortality risk score (MRS) estimators included in our panel represent next-generation clocks, were found to have low to moderate correlations with the VISAGE and Hannum models (R < 0.75), and thus may capture different aspects of epigenetic aging.</p><p><strong>Conclusions: </strong>We propose a laboratory tool that allows the quantification of DNA methylation in cytosines underlying four different clocks, thus providing broad information on epigenetic aging while maintaining a reasonable number of CpG markers, opening the way to a wide range of applications in forensics, medicine, and healthcare.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10416531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10156905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Global effects of identity and aging on the human sperm methylome. 身份和衰老对人类精子甲基组的整体影响。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-07 DOI: 10.1186/s13148-023-01541-6
Guilherme de Sena Brandine, Kenneth I Aston, Timothy G Jenkins, Andrew D Smith

Background: As the average age of fatherhood increases worldwide, so too does the need for understanding effects of aging in male germline cells. Molecular change, including epigenomic alterations, may impact offspring. Age-associated change to DNA cytosine methylation in the cytosine-guanine (CpG) context is a hallmark of aging tissues, including sperm. Prior studies have led to accurate models that predict a man's age based on specific methylation features in the DNA of sperm, but the relationship between aging and global DNA methylation in sperm remains opaque. Further clarification requires a more complete survey of the methylome with assessment of variability within and between individuals.

Results: We collected sperm methylome data in a longitudinal study of ten healthy fertile men. We used whole-genome bisulfite sequencing of samples collected 10 to 18 years apart from each donor. We found that, overall, variability between donors far exceeds age-associated variation. After controlling for donor identity, we see significant age-dependent genome-wide change to the methylome. Notably, trends of change with age depend on genomic location or annotation, with contrasting signatures that correlate with gene density and proximity to centromeres and promoter regions.

Conclusions: We uncovered epigenetic signatures that reflect a stable process which begins in early adulthood, progressing steadily through most of the male lifespan, and warrants consideration in any future study of the aging sperm epigenome.

背景:随着世界范围内成为父亲的平均年龄的增加,对男性生殖细胞衰老影响的理解需求也在增加。分子变化,包括表观基因组的改变,可能会影响后代。在胞嘧啶-鸟嘌呤(CpG)背景下,与年龄相关的DNA胞嘧啶甲基化变化是衰老组织(包括精子)的标志。先前的研究已经建立了精确的模型,根据精子DNA的特定甲基化特征来预测男性的年龄,但衰老与精子中整体DNA甲基化之间的关系仍然不清楚。进一步的澄清需要对甲基组进行更全面的调查,并评估个体内部和个体之间的变异性。结果:我们收集了10名健康育龄男性的精子甲基组数据。我们对每个供体相隔10至18年收集的样本进行了全基因组亚硫酸盐测序。我们发现,总的来说,捐献者之间的差异远远超过了与年龄相关的差异。在控制供体身份后,我们看到甲基组显著的年龄依赖性全基因组变化。值得注意的是,随年龄变化的趋势取决于基因组位置或注释,与基因密度和与着丝粒和启动子区域的接近程度相关的对比特征。结论:我们发现的表观遗传特征反映了一个稳定的过程,该过程始于成年早期,在大多数男性寿命中稳步发展,值得在未来任何衰老精子表观基因组的研究中考虑。
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引用次数: 0
Long-term environmental metal exposure is associated with hypomethylation of CpG sites in NFKB1 and other genes related to oncogenesis. 长期环境金属暴露与NFKB1中CpG位点的低甲基化和其他与肿瘤发生相关的基因有关。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-07 DOI: 10.1186/s13148-023-01536-3
Ani Stepanyan, Anna Petrackova, Siras Hakobyan, Jakub Savara, Suren Davitavyan, Eva Kriegova, Arsen Arakelyan

Background: Long-term environmental exposure to metals leads to epigenetic changes and may increase risks to human health. The relationship between the type and level of metal exposure and epigenetic changes in subjects exposed to high concentrations of metals in the environment is not yet clear. The aim of our study is to find the possible association of environmental long-term exposure to metals with DNA methylation changes of genes related to immune response and carcinogenesis. We investigated the association of plasma levels of 21 essential and non-essential metals detected by ICP-MS and the methylation level of 654 CpG sites located on NFKB1, CDKN2A, ESR1, APOA5, IGF2 and H19 genes assessed by targeted bisulfite sequencing in a cohort of 40 subjects living near metal mining area and 40 unexposed subjects. Linear regression was conducted to find differentially methylated positions with adjustment for gender, age, BMI class, smoking and metal concentration.

Results: In the metal-exposed group, five CpGs in the NFKB1 promoter region were hypomethylated compared to unexposed group. Four differentially methylated positions (DMPs) were associated with multiple metals, two of them are located on NFKB1 gene, and one each on CDKN2A gene and ESR1 gene. Two DMPs located on NFKB1 (chr4:102500951, associated with Be) and IGF2 (chr11:2134198, associated with U) are associated with specific metal levels. The methylation status of the seven CpGs located on NFKB1 (3), ESR1 (2) and CDKN2A (2) positively correlated with plasma levels of seven metals (As, Sb, Zn, Ni, U, I and Mn).

Conclusions: Our study revealed methylation changes in NFKB1, CDKN2A, IGF2 and ESR1 genes in individuals with long-term human exposure to metals. Further studies are needed to clarify the effect of environmental metal exposure on epigenetic mechanisms and pathways involved.

背景:长期环境暴露于金属会导致表观遗传变化,并可能增加对人类健康的风险。在环境中暴露于高浓度金属的受试者中,金属暴露的类型和水平与表观遗传变化之间的关系尚不清楚。我们研究的目的是发现环境长期暴露于金属与免疫反应和致癌相关基因的DNA甲基化变化之间的可能联系。我们研究了ICP-MS检测的21种必需和非必需金属的血浆水平与靶向亚硫酸盐测序评估的NFKB1、CDKN2A、ESR1、APOA5、IGF2和H19基因上654个CpG位点甲基化水平的相关性,这些位点位于金属矿区附近的40名受试者和40名未暴露的受试者中。通过线性回归分析性别、年龄、BMI等级、吸烟和金属浓度等因素对甲基化位点的影响。结果:在金属暴露组中,NFKB1启动子区域的5个CpGs与未暴露组相比低甲基化。四个差异甲基化位点(dmp)与多种金属相关,其中两个位于NFKB1基因上,CDKN2A基因和ESR1基因上各有一个。位于NFKB1 (chr4:102500951,与Be相关)和IGF2 (chr11:2134198,与U相关)上的两个DMPs与特定的金属水平相关。位于NFKB1(3)、ESR1(2)和CDKN2A(2)上的7个CpGs的甲基化状态与血浆中7种金属(As、Sb、Zn、Ni、U、I和Mn)的水平呈正相关。结论:我们的研究揭示了长期金属暴露个体中NFKB1、CDKN2A、IGF2和ESR1基因的甲基化变化。需要进一步的研究来阐明环境金属暴露对表观遗传机制和途径的影响。
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引用次数: 1
DNA methylation as a triage marker for colposcopy referral in HPV-based cervical cancer screening: a systematic review and meta-analysis. DNA 甲基化作为基于 HPV 的宫颈癌筛查中阴道镜检查转诊的分流标记:系统综述与荟萃分析。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-02 DOI: 10.1186/s13148-023-01537-2
Sofia Salta, João Lobo, Bruno Magalhães, Rui Henrique, Carmen Jerónimo

Background: Screening plays a key role in secondary prevention of cervical cancer. High-risk human papillomavirus (hrHPV) testing, a highly sensitive test but with limited specificity, has become the gold standard frontline for screening programs. Thus, the importance of effective triage strategies, including DNA methylation markers, has been emphasized. Despite the potential reported in individual studies, methylation markers still require validation before being recommended for clinical practice. This systematic review and meta-analysis aimed to evaluate the performance of DNA methylation-based biomarkers for detecting high-grade intraepithelial lesions (HSIL) in hrHPV-positive women.

Methods: Hence, PubMed, Scopus, and Cochrane databases were searched for studies that assessed methylation in hrHPV-positive women in cervical scrapes. Histologically confirmed HSIL was used as endpoint and QUADAS-2 tool enabled assessment of study quality. A bivariate random-effect model was employed to pool the estimated sensitivity and specificity as well as positive (PPV) and negative (NPV) predictive values.

Results: Twenty-three studies were included in this meta-analysis, from which cohort and referral population-based studies corresponded to nearly 65%. Most of the women analyzed were Dutch, and CADM1, FAM19A4, MAL, and miR124-2 were the most studied genes. Pooled sensitivity and specificity were 0.68 (CI 95% 0.63-0.72) and 0.75 (CI 95% 0.71-0.80) for cervical intraepithelial neoplasia (CIN) 2+ detection, respectively. For CIN3+ detection, pooled sensitivity and specificity were 0.78 (CI 95% 0.74-0.82) and 0.74 (CI 95% 0.69-0.78), respectively. For pooled prevalence, PPV for CIN2+ and CIN3+ detection were 0.514 and 0.392, respectively. Furthermore, NPV for CIN2+ and CIN3+ detection were 0.857 and 0.938, respectively.

Conclusions: This meta-analysis confirmed the great potential of DNA methylation-based biomarkers as triage tool for hrHPV-positive women in cervical cancer screening. Standardization and improved validation are, however, required. Nevertheless, these markers might represent an excellent alternative to cytology and genotyping for colposcopy referral of hrHPV-positive women, allowing for more cost-effective screening programs.

背景:筛查在宫颈癌二级预防中起着关键作用。高危人乳头瘤病毒(hrHPV)检测是一种灵敏度很高但特异性有限的检测方法,已成为筛查项目的前沿金标准。因此,包括 DNA 甲基化标记在内的有效分流策略的重要性得到了强调。尽管个别研究报告了甲基化标记物的潜力,但在推荐用于临床实践之前仍需要验证。本系统综述和荟萃分析旨在评估基于DNA甲基化的生物标记检测hrHPV阳性女性高级别上皮内病变(HSIL)的性能。以组织学确诊的HSIL为终点,采用QUADAS-2工具对研究质量进行评估。采用双变量随机效应模型对估计的敏感性、特异性以及阳性(PPV)和阴性(NPV)预测值进行汇总:本次荟萃分析共纳入 23 项研究,其中队列研究和转诊人群研究占近 65%。大多数被分析的女性是荷兰人,CADM1、FAM19A4、MAL 和 miR124-2 是研究最多的基因。宫颈上皮内瘤变(CIN)2+检测的汇总灵敏度和特异性分别为0.68(CI 95% 0.63-0.72)和0.75(CI 95% 0.71-0.80)。对于 CIN3+ 的检测,汇总灵敏度和特异性分别为 0.78(CI 95% 0.74-0.82)和 0.74(CI 95% 0.69-0.78)。就汇总患病率而言,CIN2+和CIN3+检测的PPV分别为0.514和0.392。此外,CIN2+和CIN3+检测的NPV分别为0.857和0.938:这项荟萃分析证实了基于 DNA 甲基化的生物标记物作为宫颈癌筛查中 hrHPV 阳性妇女的分诊工具的巨大潜力。不过,还需要进行标准化和改进验证。不过,这些标记物可能是细胞学和基因分型检查的绝佳替代品,可用于hrHPV阳性妇女的阴道镜检查转诊,使筛查项目更具成本效益。
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引用次数: 0
DNA methylation and 28-year cardiovascular disease risk in type 1 diabetes: the Epidemiology of Diabetes Complications (EDC) cohort study. 1 型糖尿病患者 DNA 甲基化与 28 年心血管疾病风险:糖尿病并发症流行病学 (EDC) 队列研究。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-02 DOI: 10.1186/s13148-023-01539-0
Rachel G Miller, Josyf C Mychaleckyj, Suna Onengut-Gumuscu, Eleanor Feingold, Trevor J Orchard, Tina Costacou

Background: The potential for DNA methylation (DNAm) as an early marker for cardiovascular disease (CVD) and how such an association might differ by glycemic exposure has not been examined in type 1 diabetes, a population at increased CVD risk. We thus performed a prospective epigenome-wide association study of blood leukocyte DNAm (EPIC array) and time to CVD incidence over 28 years in a childhood-onset (< 17 years) type 1 diabetes cohort, the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (n = 368 with DNA and no CVD at baseline), both overall and separately by glycemic exposure, as measured by HbA1c at baseline (split at the median: < 8.9% and ≥ 8.9%). We also assessed whether DNAm-CVD associations were independent of established cardiometabolic risk factors, including body mass index, estimated glucose disposal rate, cholesterol, triglycerides, blood pressure, pulse rate, albumin excretion rate, and estimated glomerular filtration rate.

Results: CVD (first instance of CVD death, myocardial infarction, coronary revascularization, ischemic ECG, angina, or stroke) developed in 172 participants (46.7%) over 28 years. Overall, in Cox regression models for time to CVD, none of the 683,597 CpGs examined reached significance at a false discovery rate (FDR) ≤ 0.05. In participants with HbA1c < 8.9% (n = 180), again none reached FDR ≤ 0.05, but three were associated at the a priori nominal significance level FDR ≤ 0.10: cg07147033 in MIB2, cg12324048 (intergenic, chromosome 3), and cg15883830 (intergenic, chromosome 1). In participants with HbA1c ≥ 8.9% (n = 188), two CpGs in loci involved in calcium channel activity were significantly associated with CVD (FDR ≤ 0.05): cg21823999 in GPM6A and cg23621817 in CHRNA9; four additional CpGs were nominally associated (FDR ≤ 0.10). In participants with HbA1c ≥ 8.9%, DNAm-CVD associations were only modestly attenuated after cardiometabolic risk factor adjustment, while attenuation was greater in those with HbA1c < 8.9%. No pathways were enriched in those with HbA1c < 8.9%, while pathways for calcium channel activity and integral component of synaptic membrane were significantly enriched in those with HbA1c ≥ 8.9%.

Conclusions: These results provide novel evidence that DNAm at loci involved in calcium channel activity and development may contribute to long-term CVD risk beyond known risk factors in type 1 diabetes, particularly in individuals with greater glycemic exposure, warranting further study.

背景:DNA甲基化(DNAm)作为心血管疾病(CVD)早期标志物的潜力,以及这种关联如何因血糖暴露而异,在心血管疾病风险增加的1型糖尿病人群中尚未得到研究。因此,我们对儿童期发病的 1 型糖尿病患者的血液白细胞 DNAm(EPIC 阵列)和心血管疾病发病时间进行了长达 28 年的前瞻性全表观基因组关联研究:28年间,172名参与者(46.7%)发生了心血管疾病(首次心血管疾病死亡、心肌梗死、冠状动脉血运重建、缺血性心电图、心绞痛或中风)。总体而言,在心血管疾病发生时间的 Cox 回归模型中,所检测的 683,597 个 CpGs 在假发现率 (FDR) ≤ 0.05 时均未达到显著性。结论:这些结果提供了新的证据,表明与钙通道活性和发育有关的基因位点上的DNAm可能是导致1型糖尿病患者长期心血管疾病风险的因素,而不是已知的风险因素,尤其是在血糖暴露程度较高的人群中,这值得进一步研究。
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引用次数: 0
Update on histone deacetylase inhibitors in peripheral T-cell lymphoma (PTCL). 外周t细胞淋巴瘤(PTCL)组蛋白去乙酰化酶抑制剂的最新进展。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-02 DOI: 10.1186/s13148-023-01531-8
Guang Lu, Shikai Jin, Suwen Lin, Yuping Gong, Liwen Zhang, Jingwen Yang, Weiwei Mou, Jun Du

Peripheral T-cell lymphomas (PTCLs) are a group of highly aggressive malignancies with generally poor prognoses, and the first-line chemotherapy of PTCL has limited efficacy. Currently, several novel targeted agents, including histone deacetylase inhibitors (HDACis), have been investigated to improve the therapeutic outcome of PTCLs. Several HDACis, such as romidepsin, belinostat, and chidamide, have demonstrated favorable clinical efficacy and safety in PTCLs. More novel HDACis and new combination therapies are undergoing preclinical or clinical trials. Mutation analysis based on next-generation sequencing may advance our understanding of the correlation between epigenetic mutation profiles and relevant targeted therapies. Multitargeted HDACis and HDACi-based prodrugs hold promising futures and offer further directions for drug design.

外周t细胞淋巴瘤(PTCL)是一组高度侵袭性的恶性肿瘤,通常预后较差,PTCL的一线化疗疗效有限。目前,一些新的靶向药物,包括组蛋白去乙酰化酶抑制剂(HDACis),已经被研究用于改善ptcl的治疗效果。几种HDACis,如罗米地辛、贝利诺他和奇达胺,在ptcl中显示出良好的临床疗效和安全性。更多的新型hdac和新的联合疗法正在进行临床前或临床试验。基于下一代测序的突变分析可以促进我们对表观遗传突变谱与相关靶向治疗之间关系的理解。多靶点HDACis和基于hdaci的前药前景广阔,为药物设计提供了进一步的方向。
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引用次数: 0
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Clinical Epigenetics
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