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Evaluation of pediatric epigenetic clocks across multiple tissues. 跨多个组织的儿科表观遗传时钟的评估。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-09-02 DOI: 10.1186/s13148-023-01552-3
Fang Fang, Linran Zhou, Wei Perng, Carmen J Marsit, Anna K Knight, Andres Cardenas, Max T Aung, Marie-France Hivert, Izzuddin M Aris, Jaclyn M Goodrich, Alicia K Smith, Abigail Gaylord, Rebecca C Fry, Emily Oken, George O'Connor, Douglas M Ruden, Leonardo Trasande, Julie B Herbstman, Carlos A Camargo, Nicole R Bush, Anne L Dunlop, Dana M Dabelea, Margaret R Karagas, Carrie V Breton, Carole Ober, Todd M Everson, Grier P Page, Christine Ladd-Acosta

Background: Epigenetic clocks are promising tools for assessing biological age. We assessed the accuracy of pediatric epigenetic clocks in gestational and chronological age determination.

Results: Our study used data from seven tissue types on three DNA methylation profiling microarrays and found that the Knight and Bohlin clocks performed similarly for blood cells, while the Lee clock was superior for placental samples. The pediatric-buccal-epigenetic clock performed the best for pediatric buccal samples, while the Horvath clock is recommended for children's blood cell samples. The NeoAge clock stands out for its unique ability to predict post-menstrual age with high correlation with the observed age in infant buccal cell samples.

Conclusions: Our findings provide valuable guidance for future research and development of epigenetic clocks in pediatric samples, enabling more accurate assessments of biological age.

背景:表观遗传时钟是一种很有前途的评估生物年龄的工具。我们评估了儿童表观遗传时钟在妊娠期和实足年龄测定中的准确性。结果:我们的研究使用了三种DNA甲基化分析微阵列上七种组织类型的数据,发现Knight和Bohlin时钟对血细胞的表现相似,而Lee时钟对胎盘样本的表现更优。儿科-口腔-表观遗传时钟在儿科口腔样本中表现最好,而Horvath时钟被推荐用于儿童血细胞样本。NeoAge时钟以其独特的预测月经后年龄的能力脱颖而出,与婴儿口腔细胞样本中观察到的年龄高度相关。结论:我们的研究结果为未来儿科样本表观遗传时钟的研究和开发提供了有价值的指导,可以更准确地评估生物年龄。
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引用次数: 0
Fathers' preconception smoking and offspring DNA methylation. 父亲的先入为主吸烟和后代DNA甲基化。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-31 DOI: 10.1186/s13148-023-01540-7
Negusse Tadesse Kitaba, Gerd Toril Mørkve Knudsen, Ane Johannessen, Faisal I Rezwan, Andrei Malinovschi, Anna Oudin, Bryndis Benediktsdottir, David Martino, Francisco Javier Callejas González, Leopoldo Palacios Gómez, Mathias Holm, Nils Oskar Jõgi, Shyamali C Dharmage, Svein Magne Skulstad, Sarah H Watkins, Matthew Suderman, Francisco Gómez-Real, Vivi Schlünssen, Cecilie Svanes, John W Holloway

Background: Experimental studies suggest that exposures may impact respiratory health across generations via epigenetic changes transmitted specifically through male germ cells. Studies in humans are, however, limited. We aim to identify epigenetic marks in offspring associated with father's preconception smoking.

Methods: We conducted epigenome-wide association studies (EWAS) in the RHINESSA cohort (7-50 years) on father's any preconception smoking (n = 875 offspring) and father's pubertal onset smoking < 15 years (n = 304), using Infinium MethylationEPIC Beadchip arrays, adjusting for offspring age, own smoking and maternal smoking. EWAS of maternal and offspring personal smoking were performed for comparison. Father's smoking-associated dmCpGs were checked in subpopulations of offspring who reported no personal smoking and no maternal smoking exposure.

Results: Father's smoking commencing preconception was associated with methylation of blood DNA in offspring at two cytosine-phosphate-guanine sites (CpGs) (false discovery rate (FDR) < 0.05) in PRR5 and CENPP. Father's pubertal onset smoking was associated with 19 CpGs (FDR < 0.05) mapped to 14 genes (TLR9, DNTT, FAM53B, NCAPG2, PSTPIP2, MBIP, C2orf39, NTRK2, DNAJC14, CDO1, PRAP1, TPCN1, IRS1 and CSF1R). These differentially methylated sites were hypermethylated and associated with promoter regions capable of gene silencing. Some of these sites were associated with offspring outcomes in this cohort including ever-asthma (NTRK2), ever-wheezing (DNAJC14, TPCN1), weight (FAM53B, NTRK2) and BMI (FAM53B, NTRK2) (p < 0.05). Pathway analysis showed enrichment for gene ontology pathways including regulation of gene expression, inflammation and innate immune responses. Father's smoking-associated sites did not overlap with dmCpGs identified in EWAS of personal and maternal smoking (FDR < 0.05), and all sites remained significant (p < 0.05) in analyses of offspring with no personal smoking and no maternal smoking exposure.

Conclusion: Father's preconception smoking, particularly in puberty, is associated with offspring DNA methylation, providing evidence that epigenetic mechanisms may underlie epidemiological observations that pubertal paternal smoking increases risk of offspring asthma, low lung function and obesity.

背景:实验研究表明,暴露可能通过特异性通过雄性生殖细胞传播的表观遗传变化影响几代人的呼吸健康。然而,对人类的研究是有限的。我们的目的是鉴定与父亲先入为主吸烟相关的后代的表观遗传学标记。方法:我们在RHINESSA队列(7-50岁)中对父亲的任何先入为主吸烟(n = 875个后代)和父亲青春期开始吸烟 结果:父亲吸烟开始先入为主与后代血液DNA在两个胞嘧啶磷酸鸟嘌呤位点(CpGs)的甲基化有关(错误发现率(FDR)) 结论:父亲的先入为主的吸烟,特别是在青春期,与后代DNA甲基化有关,这提供了表观遗传学机制的证据,这些机制可能是流行病学观察的基础,即青春期父亲吸烟会增加后代患哮喘、肺功能低下和肥胖的风险。
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引用次数: 0
Association of DNA methylation of vitamin D metabolic pathway related genes with colorectal cancer risk. 维生素D代谢途径相关基因的DNA甲基化与结直肠癌风险的关系
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-29 DOI: 10.1186/s13148-023-01555-0
Yi-Fan Wang, Lei Li, Xue-Qing Deng, Yu-Jing Fang, Cai-Xia Zhang

Background: Vitamin D might have anti-tumor effect, which is affected by the genes related to vitamin D metabolic pathway. Epigenetic mechanism may affect the expression level of vitamin D metabolic pathway related genes, then plays an important role in the occurrence and development of colorectal cancer. To date, no study has reported on the association between blood-based DNA methylation level of vitamin D metabolic pathway related genes and colorectal cancer risk.

Methods: A case-control study was conducted including 102 colorectal cancer cases and 102 sex- and age-frequency-matched controls in Guangzhou, China. CpG islands in the VDR, CYP24A1, CYP27B1 and CYP2R1 genes were chosen for DNA methylation analysis by MethylTarget sequencing. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of DNA methylation levels for colorectal cancer. Taking the point with the largest Youden index as the boundary value, the cumulative methylation levels of vitamin D metabolic pathway related genes were divided into hypomethylation and hypermethylation. Unconditional multivariable logistical regression model was used to calculate the adjusted odds ratio (aOR) and 95% confidence intervals (95% CIs) after adjusting for potential confounders.

Results: Among 153 CpG sites, 8 CpG sites were significantly different between the cases and the controls. The cumulative methylation level of all CpG sites in CYP2R1 was inversely associated with the risk of colorectal cancer (aOR, 0.49; 95% CI, 0.26-0.91). However, no significant association was found between cumulative methylation levels of all CpG sites in VDR, CYP24A1 and CYP27B1 and colorectal cancer risk. Significant inverse association was observed between cumulative methylation level of significant CpG sites in VDR (aOR, 0.28; 95% CI, 0.16-0.51) and CYP24A1 (aOR, 0.19; 95% CI, 0.09-0.40) and colorectal cancer risk. There were no significant associations between cumulative methylation levels of significant CpG sites in CYP2R1 and CYP27B1 and colorectal cancer risk.

Conclusions: This study indicated that the cumulative methylation levels of significant CpG sites in VDR and CYP24A1 and all CpG sites in CYP2R1 were inversely associated with colorectal cancer risk.

背景:维生素D可能具有抗肿瘤作用,其作用受维生素D代谢途径相关基因的影响。表观遗传机制可能影响维生素D代谢途径相关基因的表达水平,从而在结直肠癌的发生发展中发挥重要作用。迄今为止,还没有研究报道血液中维生素D代谢途径相关基因的DNA甲基化水平与结直肠癌风险之间的关系。方法:对广州102例结直肠癌患者和102例性别、年龄、频率匹配的对照组进行病例对照研究。选择VDR、CYP24A1、CYP27B1和CYP2R1基因中的CpG岛进行DNA甲基化分析。采用受试者工作特征(ROC)曲线评价DNA甲基化水平对结直肠癌的诊断价值。以约登指数最大的点为边界值,将维生素D代谢途径相关基因的累积甲基化水平分为低甲基化和高甲基化。在对潜在混杂因素进行校正后,采用无条件多变量逻辑回归模型计算校正优势比(aOR)和95%置信区间(95% ci)。结果:153个CpG位点中,8个CpG位点与对照组有显著性差异。CYP2R1中所有CpG位点的累积甲基化水平与结直肠癌的风险呈负相关(aOR, 0.49;95% ci, 0.26-0.91)。然而,未发现VDR、CYP24A1和CYP27B1中所有CpG位点的累积甲基化水平与结直肠癌风险之间存在显著关联。VDR中重要CpG位点的累积甲基化水平显著负相关(aOR, 0.28;95% CI, 0.16-0.51)和CYP24A1 (aOR, 0.19;95% CI, 0.09-0.40)和结直肠癌风险。CYP2R1和CYP27B1中重要CpG位点的累积甲基化水平与结直肠癌风险之间没有显著关联。结论:本研究表明,VDR和CYP24A1中重要CpG位点以及CYP2R1中所有CpG位点的累积甲基化水平与结直肠癌风险呈负相关。
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引用次数: 0
Abnormal DNA methylation analysis of leucine-rich glioma-inactivated 1 antibody encephalitis reveals novel methylation-driven genes related to prognostic and clinical features. 富亮氨酸胶质瘤失活1抗体脑炎的异常DNA甲基化分析揭示了与预后和临床特征相关的新的甲基化驱动基因。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-29 DOI: 10.1186/s13148-023-01550-5
Shan Qiao, Quanye Sun, Haiyun Li, Jie Yin, Aihua Wang, Shanchao Zhang

Background: Aberrant DNA methylation occurs commonly during pathogenesis of neuroimmunological diseases and is of clinical value in various encephalitis subtypes. However, knowledge of the impact of DNA methylation changes on pathogenesis of leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis remains limited.

Methods: A total of 44 cytokines and 10 immune checkpoint moleculars (ICMs) in the serum of patients with LGI1 encephalitis and healthy donors (HDs) were measured to evaluate the association of them with clinical parameters. Genome-wide DNA methylation profiles were performed in peripheral blood mononuclear cell (PBMC) from LGI1 encephalitis patients and HDs using reduced representation bisulfite sequencing (RRBS) and validated for the methylation status by pyrosequencing. MicroRNA profiles were acquired in serum exosome by small RNA sequencing. Targeted cytokines expression was assessed at the presence or absence of miR-2467-5p in PBMCs and the culture media, and the binding of miR-2467-5p and its targeted genes was validated by luciferase assay.

Results: There existed significant difference in 22 cytokines/chemokines and 6 ICMs between LGI1 encephalitis patients and HDs. Decreased PDCD1 with increased ICAM1 could predict unfavorable prognosis in one-year follow-up for LGI1 encephalitis patients. Fifteen of cytokines/chemokines and ICMs presented DNA-methylated changes in the promoter and gene body using RRBS in which five were verified as methylation status by pyrosequencing, and the methylation level of CSF3, CCL2, and ICAM1 was conversely associated with their expression in PBMCs. By combining RRBS data with exosome-derived microRNA sequencing, we found that hypomethylated-driven hsa-miR-2467-5p presented elevated expression in serum exosomes and PBMCs in LGI1 encephalitis. Mechanically, miR-2467-5p significantly induced reduced expression of CSF3 and PDCD1 by binding with their 3`UTR while enhanced CCL15 expression, but not significantly correlated with peripheral blood CD19 + B cell proportion of LGI1 encephalitis patients.

Conclusions: Our results provided convincing evidence for DNA methylation changes, microRNA profiles in serum exosome for LGI1 encephalitis, and we also identified several novel cytokines related to clinical features in which some represented epigenetic modification of methylated-driven pattern and microRNA modulation. Our study contributed to develop treatment for epigenetic pathogenesis in LGI1 encephalitis.

背景:异常DNA甲基化在神经免疫性疾病的发病过程中很常见,在各种脑炎亚型中具有临床价值。然而,关于DNA甲基化变化对富含亮氨酸的胶质瘤失活1 (LGI1)抗体脑炎发病机制的影响的知识仍然有限。方法:检测LGI1型脑炎患者和健康供者血清中44种细胞因子和10种免疫检查点分子(ICMs)水平,探讨其与临床参数的相关性。采用亚硫酸氢盐还原测序(RRBS)对LGI1型脑炎患者和hd患者外周血单个核细胞(PBMC)进行了全基因组DNA甲基化谱分析,并通过焦磷酸测序验证了甲基化状态。通过小RNA测序获得血清外泌体的MicroRNA谱。在pbmc和培养基中评估miR-2467-5p存在或不存在时靶向细胞因子的表达,并通过荧光素酶测定验证miR-2467-5p与其靶向基因的结合。结果:LGI1型脑炎患者与hd患者在22种细胞因子/趋化因子及6种ICMs上存在显著差异。LGI1型脑炎患者1年随访时PDCD1降低与ICAM1升高可预测预后不良。15个细胞因子/趋化因子和ICMs在启动子和基因体中出现dna甲基化变化,其中5个通过焦磷酸测序证实为甲基化状态,CSF3、CCL2和ICAM1的甲基化水平与其在PBMCs中的表达呈相反相关。通过将RRBS数据与外泌体衍生的microRNA测序相结合,我们发现低甲基化驱动的hsa-miR-2467-5p在LGI1脑炎的血清外泌体和PBMCs中表达升高。机械上,miR-2467-5p通过与CSF3和PDCD1的3'UTR结合,显著诱导CSF3和PDCD1表达降低,CCL15表达增强,但与LGI1脑炎患者外周血CD19 + B细胞比例无显著相关性。结论:我们的研究结果为LGI1脑炎的DNA甲基化变化和血清外泌体microRNA谱提供了令人信服的证据,我们还发现了一些与临床特征相关的新细胞因子,其中一些细胞因子代表了甲基化驱动模式和microRNA调节的表观遗传修饰。我们的研究有助于开发LGI1脑炎表观遗传发病机制的治疗方法。
{"title":"Abnormal DNA methylation analysis of leucine-rich glioma-inactivated 1 antibody encephalitis reveals novel methylation-driven genes related to prognostic and clinical features.","authors":"Shan Qiao, Quanye Sun, Haiyun Li, Jie Yin, Aihua Wang, Shanchao Zhang","doi":"10.1186/s13148-023-01550-5","DOIUrl":"10.1186/s13148-023-01550-5","url":null,"abstract":"<p><strong>Background: </strong>Aberrant DNA methylation occurs commonly during pathogenesis of neuroimmunological diseases and is of clinical value in various encephalitis subtypes. However, knowledge of the impact of DNA methylation changes on pathogenesis of leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis remains limited.</p><p><strong>Methods: </strong>A total of 44 cytokines and 10 immune checkpoint moleculars (ICMs) in the serum of patients with LGI1 encephalitis and healthy donors (HDs) were measured to evaluate the association of them with clinical parameters. Genome-wide DNA methylation profiles were performed in peripheral blood mononuclear cell (PBMC) from LGI1 encephalitis patients and HDs using reduced representation bisulfite sequencing (RRBS) and validated for the methylation status by pyrosequencing. MicroRNA profiles were acquired in serum exosome by small RNA sequencing. Targeted cytokines expression was assessed at the presence or absence of miR-2467-5p in PBMCs and the culture media, and the binding of miR-2467-5p and its targeted genes was validated by luciferase assay.</p><p><strong>Results: </strong>There existed significant difference in 22 cytokines/chemokines and 6 ICMs between LGI1 encephalitis patients and HDs. Decreased PDCD1 with increased ICAM1 could predict unfavorable prognosis in one-year follow-up for LGI1 encephalitis patients. Fifteen of cytokines/chemokines and ICMs presented DNA-methylated changes in the promoter and gene body using RRBS in which five were verified as methylation status by pyrosequencing, and the methylation level of CSF3, CCL2, and ICAM1 was conversely associated with their expression in PBMCs. By combining RRBS data with exosome-derived microRNA sequencing, we found that hypomethylated-driven hsa-miR-2467-5p presented elevated expression in serum exosomes and PBMCs in LGI1 encephalitis. Mechanically, miR-2467-5p significantly induced reduced expression of CSF3 and PDCD1 by binding with their 3`UTR while enhanced CCL15 expression, but not significantly correlated with peripheral blood CD19 + B cell proportion of LGI1 encephalitis patients.</p><p><strong>Conclusions: </strong>Our results provided convincing evidence for DNA methylation changes, microRNA profiles in serum exosome for LGI1 encephalitis, and we also identified several novel cytokines related to clinical features in which some represented epigenetic modification of methylated-driven pattern and microRNA modulation. Our study contributed to develop treatment for epigenetic pathogenesis in LGI1 encephalitis.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10463459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10224183","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
Correction : HTRA1 methylation in peripheral blood as a potential marker for the preclinical detection of stroke: a case-control study and a prospective nested case-control study. 纠正:外周血HTRA1甲基化作为中风临床前检测的潜在标志物:一项病例对照研究和一项前瞻性巢式病例对照研究。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-29 DOI: 10.1186/s13148-023-01558-x
Chunlan Liu, Mengxia Li, Qiming Yin, Yao Fan, Chong Shen, Rongxi Yang
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引用次数: 0
Evaluation of the pooled sample method in Infinium MethylationEPIC BeadChip array by comparison with individual samples. 通过与单个样品的比较,评估Infinium MethylationEPIC BeadChip阵列的混合样品方法。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-28 DOI: 10.1186/s13148-023-01544-3
Shota Nishitani, Takashi X Fujisawa, Akiko Yao, Shinichiro Takiguchi, Akemi Tomoda

Background: The pooled sample method is used in epigenomic research and expression analysis and is a cost-effective screening approach for small amounts of DNA. Evaluation of the pooled sample method in epigenomic studies is performed using the Illumina Infinium Methylation 450K BeadChip array; however, subsequent reports on the updated 850K array are lacking. A previous study demonstrated that the methylation levels obtained from individual samples were accurately replicated using pooled samples but did not address epigenome-wide association study (EWAS) statistics. The DNA quantification method, which is important for the homogeneous mixing of DNA in the pooled sample method, has since become fluorescence-based, and additional factors need to be considered including the resolution of batch effects of microarray chips and the heterogeneity of the cellular proportions from which the DNA samples are derived. In this study, four pooled samples were created from 44 individual samples, and EWAS statistics for differentially methylated positions (DMPs) and regions (DMRs) were conducted for individual samples and compared with the statistics obtained from the pooled samples.

Results: The methylation levels could be reproduced fairly well in the pooled samples. This was the case for the entire dataset and when limited to the top 100 CpG sites, consistent with a previous study using the 450K BeadChip array. However, the statistical results of the EWAS for the DMP by individual samples were not replicated in pooled samples. Qualitative analyses highlighting methylation within an arbitrary candidate gene were replicable. Focusing on chr 20, the statistical results of EWAS for DMR from individual samples showed replicability in the pooled samples as long as they were limited to regions with a sufficient effect size.

Conclusions: The pooled sample method replicated the methylation values well and can be used for EWAS in DMR. This method is sample amount-effective and cost-effective and can be utilized for screening by carefully understanding the effective features and disadvantages of the pooled sample method and combining it with candidate gene analyses.

背景:混合样本法用于表观基因组研究和表达分析,是一种低成本的少量DNA筛选方法。使用Illumina Infinium Methylation 450K BeadChip阵列对表观基因组研究中的混合样本方法进行评估;然而,关于更新后的850K阵列的后续报告缺乏。先前的一项研究表明,从单个样本中获得的甲基化水平可以使用汇总样本准确地复制,但没有解决全表观基因组关联研究(EWAS)统计问题。DNA定量方法对于混合样本方法中DNA的均匀混合很重要,现在已经成为基于荧光的方法,需要考虑其他因素,包括微阵列芯片批次效应的分辨率和DNA样本来源的细胞比例的异质性。在本研究中,从44个个体样本中创建了4个合并样本,并对单个样本进行了差异甲基化位置(dmp)和区域(DMRs)的EWAS统计,并与合并样本的统计结果进行了比较。结果:在混合样品中甲基化水平可以很好地重现。这是整个数据集的情况,仅限于前100个CpG站点,与之前使用450K BeadChip阵列的研究一致。然而,EWAS对单个样本的DMP的统计结果不能在合并样本中复制。定性分析强调甲基化在任意候选基因是可复制的。关注chr 20, EWAS对单个样本DMR的统计结果显示,只要它们被限制在具有足够效应量的区域,就可以在合并样本中复制。结论:混合样本法可很好地复制甲基化值,可用于DMR的EWAS。该方法具有样本量有效和成本效益高的特点,通过仔细了解混合样本法的有效特点和缺点,并结合候选基因分析,可以用于筛选。
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引用次数: 0
Objective and subjective measures of sleep initiation are differentially associated with DNA methylation in adolescents. 在青少年中,睡眠开始的客观和主观测量与DNA甲基化存在差异。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-26 DOI: 10.1186/s13148-023-01553-2
Michael Larsen, Fan He, Yuka Imamura Kawasawa, Arthur Berg, Alexandros N Vgontzas, Duanping Liao, Edward O Bixler, Julio Fernandez-Mendoza

Introduction: The onset of puberty is associated with a shift in the circadian timing of sleep, leading to delayed sleep initiation [i.e., later sleep onset time (SOT)] due to later bedtimes and/or longer sleep onset latency (SOL). Several genome-wide association studies (GWAS) have identified genes that may be involved in the etiology of sleep phenotypes. However, circadian rhythms are also epigenetically regulated; therefore, epigenetic biomarkers may provide insight into the physiology of the pubertal sleep onset shift and the pathophysiology of prolonged or delayed sleep initiation.

Results: The gene-wide analysis indicated differential methylation within or around 1818 unique genes across the sleep initiation measurements using self-report, actigraphy (ACT), and polysomnography (PSG), while GWAS-informed analysis yielded 67 genes. Gene hits were identified for bedtime (PSG), SOL (subjective, ACT and PSG) and SOT (subjective and PSG). DNA methylation within 12 genes was associated with both subjective and PSG-measured SOL, 31 with both ACT- and PSG-measured SOL, 19 with both subjective and ACT-measured SOL, and one gene (SMG1P2) had methylation sites associated with subjective, ACT- and PSG-measured SOL.

Conclusions: Objective and subjective sleep initiation in adolescents is associated with altered DNA methylation in genes previously identified in adult GWAS of sleep and circadian phenotypes. Additionally, our data provide evidence for a potential epigenetic link between habitual (subjective and ACT) SOL and in-lab SOT and DNA methylation in and around genes involved in circadian regulation (i.e., RASD1, RAI1), cardiometabolic disorders (i.e., FADS1, WNK1, SLC5A6), and neuropsychiatric disorders (i.e., PRR7, SDK1, FAM172A). If validated, these sites may provide valuable targets for early detection and prevention of disorders involving prolonged or delayed SOT, such as insomnia, delayed sleep phase, and their comorbidity.

青春期的开始与昼夜睡眠时间的变化有关,由于就寝时间较晚和/或睡眠开始潜伏期(SOL)较长,导致睡眠开始延迟[即睡眠开始时间(SOT)较晚]。一些全基因组关联研究(GWAS)已经确定了可能参与睡眠表型病因学的基因。然而,昼夜节律也受表观遗传调控;因此,表观遗传生物标志物可以为青春期睡眠开始转移的生理学和睡眠开始时间延长或延迟的病理生理学提供见解。结果:基因范围的分析表明,在使用自我报告、活动描记(ACT)和多导睡眠描记(PSG)进行的睡眠开始测量中,1818个独特基因内部或周围存在差异甲基化,而gwas的分析产生了67个基因。在就寝时间(PSG)、SOL(主观、ACT和PSG)和SOT(主观和PSG)中发现基因命中。12个基因的DNA甲基化与主观和psg测量的SOL相关,31个基因与ACT和psg测量的SOL相关,19个基因与主观和ACT测量的SOL相关,1个基因(SMG1P2)的甲基化位点与主观、ACT和psg测量的SOL相关。结论:青少年客观和主观睡眠起始与先前在成人睡眠和昼夜表型中发现的基因的DNA甲基化改变有关。此外,我们的数据为习惯性(主观和ACT) SOL和实验室SOT以及参与昼夜节律调节的基因(即RASD1, RAI1),心脏代谢疾病(即FADS1, WNK1, SLC5A6)和神经精神疾病(即PRR7, SDK1, FAM172A)中及其周围的DNA甲基化之间的潜在表观遗传联系提供了证据。如果得到证实,这些位点可能为早期发现和预防涉及延长或延迟SOT的疾病提供有价值的靶点,如失眠、睡眠阶段延迟及其合并症。
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引用次数: 0
Associations between nutrients in one-carbon metabolism and fetal DNA methylation in pregnancies with or without gestational diabetes mellitus. 有或无妊娠期糖尿病的孕妇单碳代谢营养素与胎儿DNA甲基化之间的关系
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-26 DOI: 10.1186/s13148-023-01554-1
Isma'il Kadam, Mudar Dalloul, Jeanette Hausser, Monique Huntley, Lori Hoepner, Lawrence Fordjour, Joan Hittelman, Anjana Saxena, Jia Liu, Itamar D Futterman, Howard Minkoff, Xinyin Jiang

Background: Gestational diabetes mellitus (GDM), characterized by hyperglycemia that develops during pregnancy, increases the risk of fetal macrosomia, childhood obesity and cardiometabolic disorders later in life. This process has been attributed partly to DNA methylation modifications in growth and stress-related pathways. Nutrients involved with one-carbon metabolism (OCM), such as folate, choline, betaine, and vitamin B12, provide methyl groups for DNA methylation of these pathways. Therefore, this study aimed to determine whether maternal OCM nutrient intakes and levels modified fetal DNA methylation and in turn altered fetal growth patterns in pregnancies with and without GDM.

Results: In this prospective study at a single academic institution from September 2016 to June 2019, we recruited 76 pregnant women with and without GDM at 25-33 weeks gestational age and assessed their OCM nutrient intake by diet recalls and measured maternal blood OCM nutrient levels. We also collected placenta and cord blood samples at delivery to examine fetal tissue DNA methylation of the genes that modify fetal growth and stress response such as insulin-like growth factor 2 (IGF2) and corticotropin-releasing hormone (CRH). We analyzed the association between maternal OCM nutrients and fetal DNA methylation using a generalized linear mixed model. Our results demonstrated that maternal choline intake was positively correlated with cord blood CRH methylation levels in both GDM and non-GDM pregnancies (r = 0.13, p = 0.007). Further, the downstream stress hormone cortisol regulated by CRH was inversely associated with maternal choline intake (r = - 0.36, p = 0.021). Higher maternal betaine intake and serum folate levels were associated with lower cord blood and placental IGF2 DNA methylation (r = - 0.13, p = 0.049 and r = - 0.065, p = 0.034, respectively) in both GDM and non-GDM pregnancies. Further, there was an inverse association between maternal betaine intake and birthweight of infants (r = - 0.28, p = 0.015).

Conclusions: In conclusion, we observed a complex interrelationship between maternal OCM nutrients and fetal DNA methylation levels regardless of GDM status, which may, epigenetically, program molecular pathways related to fetal growth and stress response.

背景:妊娠期糖尿病(GDM)以妊娠期高血糖为特征,增加了胎儿巨大儿、儿童肥胖和生命后期心脏代谢紊乱的风险。这一过程部分归因于生长和应激相关途径中的DNA甲基化修饰。参与单碳代谢(OCM)的营养素,如叶酸、胆碱、甜菜碱和维生素B12,为这些途径的DNA甲基化提供甲基。因此,本研究旨在确定母亲OCM营养摄入和水平是否会改变胎儿DNA甲基化,进而改变妊娠期和非妊娠期GDM胎儿的生长模式。结果:在2016年9月至2019年6月在一所学术机构进行的这项前瞻性研究中,我们招募了76名25-33周孕龄的有或无GDM的孕妇,通过饮食回顾评估她们的OCM营养摄入量,并测量了母体血液OCM营养水平。我们还收集了分娩时的胎盘和脐带血样本,以检测胎儿组织中改变胎儿生长和应激反应的基因(如胰岛素样生长因子2 (IGF2)和促肾上腺皮质激素释放激素(CRH))的DNA甲基化。我们使用广义线性混合模型分析了母体OCM营养素与胎儿DNA甲基化之间的关系。我们的研究结果表明,母亲胆碱摄入量与GDM和非GDM妊娠的脐带血CRH甲基化水平呈正相关(r = 0.13, p = 0.007)。此外,CRH调节的下游应激激素皮质醇与母体胆碱摄入量呈负相关(r = - 0.36, p = 0.021)。在妊娠期糖尿病和非妊娠期糖尿病孕妇中,较高的母亲甜菜碱摄入量和血清叶酸水平与较低的脐带血和胎盘IGF2 DNA甲基化相关(r = - 0.13, p = 0.049和r = - 0.065, p = 0.034)。此外,母亲甜菜碱摄入量与婴儿出生体重呈负相关(r = - 0.28, p = 0.015)。结论:总之,我们观察到无论GDM状态如何,母体OCM营养素与胎儿DNA甲基化水平之间存在复杂的相互关系,这可能在表观遗传学上编程了与胎儿生长和应激反应相关的分子途径。
{"title":"Associations between nutrients in one-carbon metabolism and fetal DNA methylation in pregnancies with or without gestational diabetes mellitus.","authors":"Isma'il Kadam, Mudar Dalloul, Jeanette Hausser, Monique Huntley, Lori Hoepner, Lawrence Fordjour, Joan Hittelman, Anjana Saxena, Jia Liu, Itamar D Futterman, Howard Minkoff, Xinyin Jiang","doi":"10.1186/s13148-023-01554-1","DOIUrl":"10.1186/s13148-023-01554-1","url":null,"abstract":"<p><strong>Background: </strong>Gestational diabetes mellitus (GDM), characterized by hyperglycemia that develops during pregnancy, increases the risk of fetal macrosomia, childhood obesity and cardiometabolic disorders later in life. This process has been attributed partly to DNA methylation modifications in growth and stress-related pathways. Nutrients involved with one-carbon metabolism (OCM), such as folate, choline, betaine, and vitamin B<sub>12</sub>, provide methyl groups for DNA methylation of these pathways. Therefore, this study aimed to determine whether maternal OCM nutrient intakes and levels modified fetal DNA methylation and in turn altered fetal growth patterns in pregnancies with and without GDM.</p><p><strong>Results: </strong>In this prospective study at a single academic institution from September 2016 to June 2019, we recruited 76 pregnant women with and without GDM at 25-33 weeks gestational age and assessed their OCM nutrient intake by diet recalls and measured maternal blood OCM nutrient levels. We also collected placenta and cord blood samples at delivery to examine fetal tissue DNA methylation of the genes that modify fetal growth and stress response such as insulin-like growth factor 2 (IGF2) and corticotropin-releasing hormone (CRH). We analyzed the association between maternal OCM nutrients and fetal DNA methylation using a generalized linear mixed model. Our results demonstrated that maternal choline intake was positively correlated with cord blood CRH methylation levels in both GDM and non-GDM pregnancies (r = 0.13, p = 0.007). Further, the downstream stress hormone cortisol regulated by CRH was inversely associated with maternal choline intake (r = - 0.36, p = 0.021). Higher maternal betaine intake and serum folate levels were associated with lower cord blood and placental IGF2 DNA methylation (r = - 0.13, p = 0.049 and r = - 0.065, p = 0.034, respectively) in both GDM and non-GDM pregnancies. Further, there was an inverse association between maternal betaine intake and birthweight of infants (r = - 0.28, p = 0.015).</p><p><strong>Conclusions: </strong>In conclusion, we observed a complex interrelationship between maternal OCM nutrients and fetal DNA methylation levels regardless of GDM status, which may, epigenetically, program molecular pathways related to fetal growth and stress response.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10182902","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: 2
The inactive X chromosome accumulates widespread epigenetic variability with age. 无活性的X染色体随着年龄的增长积累了广泛的表观遗传变异。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-25 DOI: 10.1186/s13148-023-01549-y
Yunfeng Liu, Lucy Sinke, Thomas H Jonkman, Roderick C Slieker, Erik W van Zwet, Lucia Daxinger, Bastiaan T Heijmans

Background: Loss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome in females through DNA methylation. Hence, age-related disruption of X-chromosome inactivation (XCI) may contribute to the aging process in women.

Methods: We analyzed 9,777 CpGs on the X chromosome in whole blood samples from 2343 females and 1688 males (Illumina 450k methylation array) and replicated findings in duplicate using one whole blood and one purified monocyte data set (in total, 991/924 females/males). We used double generalized linear models to detect age-related differentially methylated CpGs (aDMCs), whose mean methylation level differs with age, and age-related variably methylated CpGs (aVMCs), whose methylation level becomes more variable with age.

Results: In females, aDMCs were relatively uncommon (n = 33) and preferentially occurred in regions known to escape XCI. In contrast, many CpGs (n = 987) were found to display an increased variance with age (aVMCs). Of note, the replication rate of aVMCs was also high in purified monocytes (94%), indicating an independence of cell composition. aVMCs accumulated in CpG islands and regions subject to XCI suggesting that they stemmed from the inactive X. In males, carrying an active copy of the X chromosome only, aDMCs (n = 316) were primarily driven by cell composition, while aVMCs replicated well (95%) but were infrequent (n = 37).

Conclusions: Our results imply that age-related DNA methylation differences at the inactive X chromosome are dominated by the accumulation of variability.

背景:表观遗传控制的丧失是衰老的标志。表观遗传机制中最突出的作用是通过DNA甲基化使雌性X染色体的两个拷贝中的一个失活。因此,年龄相关的x染色体失活(XCI)的破坏可能有助于女性的衰老过程。方法:利用Illumina 450k甲基化阵列(Illumina 450k methylation array)对2343名女性和1688名男性的全血样本中X染色体上的9777个CpGs进行分析,并使用一个全血和一个纯化单核细胞数据集(共991/924名女性/男性)重复分析结果。我们使用双广义线性模型检测年龄相关的差异甲基化CpGs (aDMCs),其平均甲基化水平随年龄而变化,以及年龄相关的可变甲基化CpGs (aVMCs),其甲基化水平随年龄变化更大。结果:在女性中,admc相对不常见(n = 33),并且优先发生在已知逃避XCI的区域。相比之下,许多cpg (n = 987)显示出随年龄增加的方差(avmc)。值得注意的是,avmc在纯化单核细胞中的复制率也很高(94%),表明细胞组成的独立性。avmc在CpG岛和受XCI影响的区域积累,表明它们起源于失活的X染色体。在雄性中,仅携带一条X染色体的活跃拷贝,admc (n = 316)主要由细胞组成驱动,而avmc复制良好(95%),但不常见(n = 37)。结论:我们的研究结果表明,非活性X染色体上与年龄相关的DNA甲基化差异主要是由变异性的积累引起的。
{"title":"The inactive X chromosome accumulates widespread epigenetic variability with age.","authors":"Yunfeng Liu, Lucy Sinke, Thomas H Jonkman, Roderick C Slieker, Erik W van Zwet, Lucia Daxinger, Bastiaan T Heijmans","doi":"10.1186/s13148-023-01549-y","DOIUrl":"10.1186/s13148-023-01549-y","url":null,"abstract":"<p><strong>Background: </strong>Loss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome in females through DNA methylation. Hence, age-related disruption of X-chromosome inactivation (XCI) may contribute to the aging process in women.</p><p><strong>Methods: </strong>We analyzed 9,777 CpGs on the X chromosome in whole blood samples from 2343 females and 1688 males (Illumina 450k methylation array) and replicated findings in duplicate using one whole blood and one purified monocyte data set (in total, 991/924 females/males). We used double generalized linear models to detect age-related differentially methylated CpGs (aDMCs), whose mean methylation level differs with age, and age-related variably methylated CpGs (aVMCs), whose methylation level becomes more variable with age.</p><p><strong>Results: </strong>In females, aDMCs were relatively uncommon (n = 33) and preferentially occurred in regions known to escape XCI. In contrast, many CpGs (n = 987) were found to display an increased variance with age (aVMCs). Of note, the replication rate of aVMCs was also high in purified monocytes (94%), indicating an independence of cell composition. aVMCs accumulated in CpG islands and regions subject to XCI suggesting that they stemmed from the inactive X. In males, carrying an active copy of the X chromosome only, aDMCs (n = 316) were primarily driven by cell composition, while aVMCs replicated well (95%) but were infrequent (n = 37).</p><p><strong>Conclusions: </strong>Our results imply that age-related DNA methylation differences at the inactive X chromosome are dominated by the accumulation of variability.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10116756","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: 2
Cell-free DNA 5-hydroxymethylcytosine is highly sensitive for MRD assessment in acute myeloid leukemia. 无细胞DNA 5-羟甲基胞嘧啶对急性髓系白血病的MRD评估高度敏感。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-08-24 DOI: 10.1186/s13148-023-01547-0
Jianming Shao, Shilpan Shah, Siddhartha Ganguly, Youli Zu, Chuan He, Zejuan Li

Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML). However, MRD cannot be detected in many patients using current methods. We developed a highly sensitive 5-hydroxymethylcytosine (5hmC) signature in cell-free DNA by analyzing 115 AML patients and 86 controls. The 5hmC method detected MRD in 20 of 29 patients with negative MRD by multiparameter flow cytometry and 11 of 14 patients with negative MRD by molecular methods. MRD detection by the 5hmC method was significantly associated with relapse-free survival. This novel method can be used in most AML patients and may significantly impact AML patient management.

可测量残留病(MRD)是急性髓性白血病(AML)的重要生物标志物。然而,目前的方法无法在许多患者中检测到MRD。通过分析115名AML患者和86名对照,我们在无细胞DNA中发现了高度敏感的5-羟甲基胞嘧啶(5hmC)特征。5hmC方法对29例MRD阴性患者中的20例(多参数流式细胞术)和14例MRD阴性患者中的11例(分子法)进行MRD检测。5hmC方法的MRD检测与无复发生存率显著相关。这种新方法可用于大多数AML患者,并可能对AML患者的管理产生重大影响。
{"title":"Cell-free DNA 5-hydroxymethylcytosine is highly sensitive for MRD assessment in acute myeloid leukemia.","authors":"Jianming Shao, Shilpan Shah, Siddhartha Ganguly, Youli Zu, Chuan He, Zejuan Li","doi":"10.1186/s13148-023-01547-0","DOIUrl":"10.1186/s13148-023-01547-0","url":null,"abstract":"<p><p>Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML). However, MRD cannot be detected in many patients using current methods. We developed a highly sensitive 5-hydroxymethylcytosine (5hmC) signature in cell-free DNA by analyzing 115 AML patients and 86 controls. The 5hmC method detected MRD in 20 of 29 patients with negative MRD by multiparameter flow cytometry and 11 of 14 patients with negative MRD by molecular methods. MRD detection by the 5hmC method was significantly associated with relapse-free survival. This novel method can be used in most AML patients and may significantly impact AML patient management.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10116734","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
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Clinical Epigenetics
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