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Stress-induced epigenetic effects driven by maternal lactation in dairy cattle: a comethylation network approach. 由母体泌乳驱动的奶牛压力诱导表观遗传效应:组合甲基化网络方法。
IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-07-23 DOI: 10.1080/15592294.2024.2381856
Adrián López-Catalina, Antonio Reverter, Pamela A Alexandre, Loan T Nguyen, Oscar González-Recio

Epigenetic marks do not follow the Mendelian laws of inheritance. The environment can alter the epigenotype of an individual when exposed to different external stressors. In lactating cows, the first stages of gestation overlap with the lactation peak, creating a negative energy balance that is difficult to overcome with diet. This negative energy balance could affect early embryo development that must compete with the mammary tissue for nutrients. We hypothesize that the methylation profiles of calves born to nonlactating heifers are different from those of calves born to lactating cows. We found 50,277 differentially methylated cytosines and 2,281 differentially methylated regions between these two groups of animals. A comethylation network was constructed to study the correlation between the phenotypes of the mothers and the epigenome of the calves, revealing 265 regions associated with the phenotypes. Our study revealed the presence of DMCs and DMRs in calves gestated by heifers and lactating cows, which were linked to the dam's lactation and the calves' ICAP and milk EBV. Gene-specific analysis highlighted associations with vasculature and organ morphogenesis and cell communication and signalling. These finding support the hypothesis that calves gestated by nonlactating mothers have a different methylation profile than those gestated by lactating cows.

表观遗传标记并不遵循孟德尔遗传定律。当暴露于不同的外部压力时,环境会改变个体的表观基因型。在泌乳奶牛中,妊娠的最初阶段与泌乳高峰期重叠,会产生难以通过饮食克服的负能量平衡。这种负能量平衡可能会影响早期胚胎的发育,因为胚胎必须与乳腺组织争夺营养。我们假设,非泌乳母牛所生犊牛的甲基化图谱与泌乳母牛所生犊牛的甲基化图谱不同。我们在这两组动物之间发现了 50,277 个不同的甲基化胞嘧啶和 2,281 个不同的甲基化区域。为了研究母牛表型与小牛表观基因组之间的相关性,我们构建了一个组合甲基化网络,发现了与表型相关的 265 个区域。我们的研究揭示了母牛和泌乳牛所产犊牛中存在的DMCs和DMRs,它们与母牛的泌乳期、犊牛的ICAP和牛奶EBV有关。基因特异性分析强调了与血管和器官形态发生以及细胞通讯和信号传导的关联。这些发现支持了一个假设,即非泌乳母牛妊娠的犊牛与泌乳母牛妊娠的犊牛具有不同的甲基化特征。
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引用次数: 0
LncRNA NEAT1 aggravates human microvascular endothelial cell injury by inhibiting the Apelin/Nrf2/HO-1 signalling pathway in type 2 diabetes mellitus with obstructive sleep apnoea. LncRNA NEAT1 通过抑制阻塞性睡眠呼吸暂停的 2 型糖尿病患者的 Apelin/Nrf2/HO-1 信号通路,加重人体微血管内皮细胞损伤。
IF 3.7 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-12-01 Epub Date: 2024-01-17 DOI: 10.1080/15592294.2023.2293409
Kai Chen, Baiqing Ou, Quan Huang, Daqing Deng, Yi Xiang, Fang Hu

Long noncoding RNAs (lncRNAs) regulate the progression of type 2 diabetes mellitus complicated with obstructive sleep apnoea (T2DM-OSA). However, the role of the lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in T2DM-OSA remains unknown. This study aimed to reveal the function of NEAT1 in T2DM-OSA and the underlying mechanism. KKAy mice were exposed to intermittent hypoxia (IH) or intermittent normoxia to generate a T2DM-OSA mouse model. HMEC-1 cells were treated with high glucose (HG) and IH to construct a T2DM-OSA cell model. RNA expression was detected by qRT-PCR. The protein expression of Apelin, NF-E2-related factor 2 (Nrf2), haem oxygenase-1 (HO-1), and up-frameshift suppressor 1 (UPF1) was assessed using western blot. Cell injury was evaluated using flow cytometry, enzyme-linked immunosorbent assay, and oxidative stress kit assays. RIP, RNA pull-down, and actinomycin D assays were performed to determine the associations between NEAT1, UPF1, and Apelin. NEAT1 expression was upregulated in the aortic vascular tissues of mice with T2DM exposed to IH and HMEC-1 cells stimulated with HG and IH, whereas Apelin expression was downregulated. The absence of NEAT1 protected HMEC-1 cells from HG- and IH-induced damage. Furthermore, NEAT1 destabilized Apelin mRNA by recruiting UPF1. Apelin overexpression decreased HG- and IH-induced injury to HMEC-1 cells by activating the Nrf2/HO-1 pathway. Moreover, NEAT1 knockdown reduced HG- and IH-induced injury to HMEC-1 cells through Apelin. NEAT1 silencing reduced HMEC-1 cell injury through the Apelin/Nrf2/HO-1 signalling pathway in T2DM-OSA.Abbreviations: LncRNAs, long non-coding RNAs; T2DM, type 2 diabetes mellitus; OSA, obstructive sleep apnoea; NEAT1, nuclear paraspeckle assembly transcript 1; IH, intermittent hypoxia; HMEC-1, human microvascular endothelial cells; HG, high glucose; Nrf2, NF-E2-related factor 2; UPF1, up-frameshift suppressor 1; HO-1, haem oxygenase-1; qRT-PCR, quantitative real-time polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; TNF-α, tumour necrosis factor-α; CCK-8, Cell Counting Kit-8; IL-1β, interleukin-1β; ROS, reactive oxygen species; MDA, malondialdehyde; SOD, superoxide dismutase; RIP, RNA immunoprecipitation; SD, standard deviations; GSH, glutathione; AIS, acute ischaemic stroke; HMGB1, high mobility group box-1 protein; TLR4, toll-like receptor 4.

长非编码 RNA(lncRNA)可调控 2 型糖尿病并发阻塞性睡眠呼吸暂停(T2DM-OSA)的进展。然而,lncRNA核旁斑块组装转录本1(NEAT1)在T2DM-OSA中的作用仍然未知。本研究旨在揭示 NEAT1 在 T2DM-OSA 中的功能及其内在机制。将 KKAy 小鼠暴露于间歇性低氧(IH)或间歇性常氧,以产生 T2DM-OSA 小鼠模型。用高糖(HG)和IH处理HMEC-1细胞,构建T2DM-OSA细胞模型。通过 qRT-PCR 检测 RNA 表达。用 Western 印迹法评估了 Apelin、NF-E2 相关因子 2(Nrf2)、血氧合酶-1(HO-1)和上帧移位抑制因子 1(UPF1)的蛋白表达。细胞损伤采用流式细胞术、酶联免疫吸附测定法和氧化应激试剂盒测定法进行评估。为了确定 NEAT1、UPF1 和 Apelin 之间的关联,还进行了 RIP、RNA 拉取和放线菌素 D 检测。在暴露于 IH 的 T2DM 小鼠主动脉血管组织和受到 HG 和 IH 刺激的 HMEC-1 细胞中,NEAT1 表达上调,而 Apelin 表达下调。NEAT1 的缺失可保护 HMEC-1 细胞免受 HG 和 IH 诱导的损伤。此外,NEAT1 通过招募 UPF1 使 Apelin mRNA 失稳。Apelin 的过表达可通过激活 Nrf2/HO-1 通路减少 HG 和 IH 诱导的 HMEC-1 细胞损伤。此外,敲除 NEAT1 可通过 Apelin 减少 HG 和 IH 诱导的对 HMEC-1 细胞的损伤。在T2DM-OSA中,沉默NEAT1可通过Apelin/Nrf2/HO-1信号通路减少HMEC-1细胞损伤:缩写:LncRNAs,长非编码 RNAs;T2DM,2 型糖尿病;OSA,阻塞性睡眠呼吸暂停;NEAT1,核旁斑块组装转录本 1;IH,间歇性缺氧;HMEC-1,人微血管内皮细胞;HG,高血糖;Nrf2,NF-E2 相关因子 2;UPF1,上移抑制因子 1;HO-1,血氧合酶-1;qRT-PCR,定量实时聚合酶链反应;ELISA,酶联免疫吸附试验;GAPDH,3-磷酸甘油醛脱氢酶;TNF-α,肿瘤坏死因子-α;CCK-8,细胞计数试剂盒-8;IL-1β,白细胞介素-1β;ROS,活性氧;MDA,丙二醛;SOD:超氧化物歧化酶;RIP:RNA 免疫沉淀;SD:标准差;GSH:谷胱甘肽;AIS:急性缺血性中风;HMGB1:高迁移率组盒-1 蛋白;TLR4:收费样受体 4。
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引用次数: 0
MIMOSA: a resource consisting of improved methylome prediction models increases power to identify DNA methylation-phenotype associations. MIMOSA:由改进的甲基组预测模型组成的资源,提高了识别 DNA 甲基化与表型关联的能力。
IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-07-04 DOI: 10.1080/15592294.2024.2370542
Hunter J Melton, Zichen Zhang, Hong-Wen Deng, Lang Wu, Chong Wu

Although DNA methylation (DNAm) has been implicated in the pathogenesis of numerous complex diseases, from cancer to cardiovascular disease to autoimmune disease, the exact methylation sites that play key roles in these processes remain elusive. One strategy to identify putative causal CpG sites and enhance disease etiology understanding is to conduct methylome-wide association studies (MWASs), in which predicted DNA methylation that is associated with complex diseases can be identified. However, current MWAS models are primarily trained using the data from single studies, thereby limiting the methylation prediction accuracy and the power of subsequent association studies. Here, we introduce a new resource, MWAS Imputing Methylome Obliging Summary-level mQTLs and Associated LD matrices (MIMOSA), a set of models that substantially improve the prediction accuracy of DNA methylation and subsequent MWAS power through the use of a large summary-level mQTL dataset provided by the Genetics of DNA Methylation Consortium (GoDMC). Through the analyses of GWAS (genome-wide association study) summary statistics for 28 complex traits and diseases, we demonstrate that MIMOSA considerably increases the accuracy of DNA methylation prediction in whole blood, crafts fruitful prediction models for low heritability CpG sites, and determines markedly more CpG site-phenotype associations than preceding methods. Finally, we use MIMOSA to conduct a case study on high cholesterol, pinpointing 146 putatively causal CpG sites.

尽管 DNA 甲基化(DNAm)与癌症、心血管疾病、自身免疫性疾病等多种复杂疾病的发病机制有关,但在这些过程中发挥关键作用的确切甲基化位点仍然难以确定。确定推定的致病 CpG 位点并加深对疾病病因学认识的一种策略是进行全甲基化组关联研究(MWAS),通过该研究可以确定与复杂疾病相关的预测 DNA 甲基化。然而,目前的 MWAS 模型主要使用单项研究的数据进行训练,因此限制了甲基化预测的准确性和后续关联研究的能力。在此,我们介绍一种新资源--MWAS Imputing Methylome Obliging Summary-level mQTLs and Associated LD matrices (MIMOSA),这是一套通过使用 DNA 甲基化遗传学联合会(GoDMC)提供的大型摘要级 mQTL 数据集来大幅提高 DNA 甲基化预测准确性和后续 MWAS 功率的模型。通过分析 28 种复杂性状和疾病的 GWAS(全基因组关联研究)汇总统计数据,我们证明 MIMOSA 大大提高了全血中 DNA 甲基化预测的准确性,为低遗传率 CpG 位点创建了富有成效的预测模型,并且与之前的方法相比,确定了明显更多的 CpG 位点-表型关联。最后,我们利用 MIMOSA 进行了一项关于高胆固醇的案例研究,精确定位了 146 个可能的致病 CpG 位点。
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引用次数: 0
Direction-aware functional class scoring enrichment analysis of infinium DNA methylation data. 对无限DNA甲基化数据进行方向感知功能分类评分富集分析。
IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-07-05 DOI: 10.1080/15592294.2024.2375022
Mark Ziemann, Mandhri Abeysooriya, Anusuiya Bora, Séverine Lamon, Mary Sravya Kasu, Mitchell W Norris, Yen Ting Wong, Jeffrey M Craig

Infinium Methylation BeadChip arrays remain one of the most popular platforms for epigenome-wide association studies, but tools for downstream pathway analysis have their limitations. Functional class scoring (FCS) is a group of pathway enrichment techniques that involve the ranking of genes and evaluation of their collective regulation in biological systems, but the implementations described for Infinium methylation array data do not retain direction information, which is important for mechanistic understanding of genomic regulation. Here, we evaluate several candidate FCS methods that retain directional information. According to simulation results, the best-performing method involves the mean aggregation of probe limma t-statistics by gene followed by a rank-ANOVA enrichment test using the mitch package. This method, which we call 'LAM,' outperformed an existing over-representation analysis method in simulations, and showed higher sensitivity and robustness in an analysis of real lung tumour-normal paired datasets. Using matched RNA-seq data, we examine the relationship of methylation differences at promoters and gene bodies with RNA expression at the level of pathways in lung cancer. To demonstrate the utility of our approach, we apply it to three other contexts where public data were available. First, we examine the differential pathway methylation associated with chronological age. Second, we investigate pathway methylation differences in infants conceived with in vitro fertilization. Lastly, we analyse differential pathway methylation in 19 disease states, identifying hundreds of novel associations. These results show LAM is a powerful method for the detection of differential pathway methylation complementing existing methods. A reproducible vignette is provided to illustrate how to implement this method.

Infinium 甲基化芯片阵列仍然是最流行的表观基因组关联研究平台之一,但用于下游通路分析的工具有其局限性。功能分类评分(FCS)是一组通路富集技术,涉及基因排序和评估它们在生物系统中的集体调控,但针对 Infinium 甲基化阵列数据描述的实现方法不保留方向信息,而方向信息对于从机理上理解基因组调控非常重要。在此,我们评估了几种保留方向信息的候选 FCS 方法。根据模拟结果,表现最好的方法是按基因对探针 limma t 统计量进行平均聚合,然后使用 mitch 软件包进行秩-ANOVA 富集检验。我们称这种方法为 "LAM",它在模拟中的表现优于现有的过度代表性分析方法,并在真实肺部肿瘤-正常配对数据集的分析中表现出更高的灵敏度和稳健性。利用匹配的 RNA-seq 数据,我们研究了启动子和基因体的甲基化差异与肺癌通路水平的 RNA 表达之间的关系。为了证明我们的方法的实用性,我们将其应用到了其他三个有公开数据的领域。首先,我们研究了与年龄相关的不同通路甲基化。其次,我们研究了体外受精婴儿的通路甲基化差异。最后,我们分析了 19 种疾病状态中不同的通路甲基化,发现了数百种新的关联。这些结果表明,LAM 是一种检测不同通路甲基化的强大方法,是对现有方法的补充。我们提供了一个可重复的小故事来说明如何实施这种方法。
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引用次数: 0
m6A reader YTHDC2 mediates NCOA4 mRNA stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhage. m6A 阅读器 YTHDC2 介导 NCOA4 mRNA 的稳定性,影响铁蛋白吞噬,从而减轻脑出血后的继发性损伤。
IF 3.7 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-12-01 Epub Date: 2024-03-11 DOI: 10.1080/15592294.2024.2326868
Fengfeng Li, Fang Wang, Lei Wang, Jianhua Wang, Shanshan Wei, Junjun Meng, Yanan Li, Lei Feng, Pei Jiang

Oxidative stress and neuronal dysfunction caused by intracerebral haemorrhage (ICH) can lead to secondary injury. The m6A modification has been implicated in the progression of ICH. This study aimed to investigate the role of the m6A reader YTHDC2 in ICH-induced secondary injury. ICH models were established in rats using autologous blood injection, and neuronal cell models were induced with Hemin. Experiments were conducted to overexpress YTH domain containing 2 (YTHDC2) and examine its effects on neuronal dysfunction, brain injury, and neuronal ferritinophagy. RIP-qPCR and METTL3 silencing were performed to investigate the regulation of YTHDC2 on nuclear receptor coactivator 4 (NCOA4). Finally, NCOA4 overexpression was used to validate the regulatory mechanism of YTHDC2 in ICH. The study found that YTHDC2 expression was significantly downregulated in the brain tissues of ICH rats. However, YTHDC2 overexpression improved neuronal dysfunction and reduced brain water content and neuronal death after ICH. Additionally, it reduced levels of ROS, NCOA4, PTGS2, and ATG5 in the brain tissues of ICH rats, while increasing levels of FTH and FTL. YTHDC2 overexpression also decreased levels of MDA and Fe2+ in the serum, while promoting GSH synthesis. In neuronal cells, YTHDC2 overexpression alleviated Hemin-induced injury, which was reversed by Erastin. Mechanistically, YTHDC2-mediated m6A modification destabilized NCOA4 mRNA, thereby reducing ferritinophagy and alleviating secondary injury after ICH. However, the effects of YTHDC2 were counteracted by NCOA4 overexpression. Overall, YTHDC2 plays a protective role in ICH-induced secondary injury by regulating NCOA4-mediated ferritinophagy.

脑内出血(ICH)引起的氧化应激和神经元功能障碍可导致继发性损伤。m6A 修饰与 ICH 的进展有关。本研究旨在探讨 m6A 阅读器 YTHDC2 在 ICH 诱导的继发性损伤中的作用。研究人员利用自体血注射建立了大鼠 ICH 模型,并用 Hemin 诱导了神经元细胞模型。实验过表达含YTH结构域的2(YTHDC2)并检测其对神经元功能障碍、脑损伤和神经元噬铁性的影响。研究人员进行了 RIP-qPCR 和 METTL3 沉默,以研究 YTHDC2 对核受体辅激活子 4(NCOA4)的调控。最后,通过过表达 NCOA4 验证了 YTHDC2 在 ICH 中的调控机制。研究发现,YTHDC2在ICH大鼠脑组织中的表达明显下调。然而,过表达 YTHDC2 可改善 ICH 后神经元功能障碍,降低脑含水量和神经元死亡。此外,它还降低了 ICH 大鼠脑组织中 ROS、NCOA4、PTGS2 和 ATG5 的水平,同时提高了 FTH 和 FTL 的水平。过表达 YTHDC2 还能降低血清中 MDA 和 Fe2+ 的水平,同时促进 GSH 的合成。在神经细胞中,过表达 YTHDC2 可减轻 Hemin 诱导的损伤,而 Erastin 可逆转这种损伤。从机制上讲,YTHDC2 介导的 m6A 修饰破坏了 NCOA4 mRNA 的稳定性,从而减少了铁蛋白吞噬,减轻了 ICH 后的继发性损伤。然而,NCOA4 的过表达抵消了 YTHDC2 的作用。总之,YTHDC2 通过调节 NCOA4 介导的嗜铁蛋白,在 ICH 诱导的继发性损伤中发挥保护作用。
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引用次数: 0
PRKCB methylation: a potential biomarker of MDD with childhood chronic stress, a cross-sectional study in drug-naive, first-episode adolescent MDD. PRKCB 甲基化:伴有童年慢性压力的 MDD 的潜在生物标志物,一项针对药物无效、首次发病的青少年 MDD 的横断面研究。
IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-09-29 DOI: 10.1080/15592294.2024.2408159
Yuanmei Tao, Meijiang Jin, Hang Zhang, Maojia Ran, Hanmei Xu, Shoukang Zou, Fang Deng, Lijuan Huang, Hong Zhang, Xiaolan Wang, Yanping Wang, Huijin Hou, Shufang Liang, Xiaohong Ma, Li Yin

The purpose of this study was to investigate the relationship between childhood chronic stress(CCS), Protein kinase C beta (PRKCB) methylation and adolescent major depressive disorder (MDD). After recruiting 100 adolescents with MDD and 50 healthy controls (HCs), we evaluated the severity of CCS. PRKCB methylation was assessed by pyrosequencing using whole blood-derived DNA. To explore the relationship between CCS, PRKCB and adolescent MDD, we conducted correlation analysis and regression analysis, and constructed multiplicative interaction models and generalized linear models. PRKCB methylation and CCS were both found to be associated with MDD, and CCS was associated with PRKCB methylation. No significant CCS-PRKCB methylation interactions were observed. However, we found the interaction of CCS and MDD on PRKCB methylation. Our results found that PRKCB methylation was influenced by CCS and the disease itself, and PRKCB methylation was significantly positively associated with MDD severity, suggesting that PRKCB methylation may be a potential biomarker for adolescent MDD. This study is a cross-sectional observational study, which cannot draw the conclusion of causality. Prospective cohort studies are needed to further examine the relationship between CCS, adolescent MDD, and PRKCB methylation.

本研究旨在探讨童年慢性压力(CCS)、蛋白激酶C beta(PRKCB)甲基化与青少年重度抑郁障碍(MDD)之间的关系。在招募了100名患有重度抑郁症的青少年和50名健康对照组(HCs)后,我们评估了CCS的严重程度。我们使用全血DNA热测序法评估了PRKCB甲基化情况。为了探讨CCS、PRKCB和青少年MDD之间的关系,我们进行了相关分析和回归分析,并构建了乘法交互模型和广义线性模型。结果发现,PRKCB 甲基化和 CCS 均与 MDD 相关,而 CCS 与 PRKCB 甲基化相关。没有观察到 CCS 与 PRKCB 甲基化之间有明显的交互作用。但是,我们发现 CCS 和 MDD 对 PRKCB 甲基化有交互作用。我们的结果发现,PRKCB甲基化受CCS和疾病本身的影响,PRKCB甲基化与MDD严重程度呈显著正相关,这表明PRKCB甲基化可能是青少年MDD的潜在生物标志物。本研究是一项横断面观察性研究,不能得出因果关系的结论。需要进行前瞻性队列研究,以进一步探讨CCS、青少年多发性抑郁症和PRKCB甲基化之间的关系。
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引用次数: 0
Detection of DNA methylation from buccal swabs using nanopore sequencing to study stunting. 利用纳米孔测序技术检测口腔拭子中的 DNA 甲基化,以研究发育迟缓问题。
IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-11-03 DOI: 10.1080/15592294.2024.2418717
Alim El-Hakim, Inswasti Cahyani, Muhammad Zulfikar Arief, Gilang Akbariani, Asep Muhamad Ridwanuloh, Syam Budi Iryanto, Ratih Rahayu, Daeng Deni Mardaeni, Vincentius Budhyanto, Yusnita, Wening Sari, Anggi Pn Hidayati, Intan Razari, Silviatun Nihayah, Kinasih Prayuni, Chandra Utomo, Ratih Asmana Ningrum, Susanti Susanti, Ahmad Utomo

Stunting is the result of chronic malnutrition due to the lack of micronutrient-based methyl donors required for epigenetic programming during the first 1000 days of life. Methylation studies using bisulfite conversion from blood DNA are invasive and may not be practical for large-scale epidemiological investigation or nutrition intervention programs. Buccal epithelial methylation may reflect early germline methylation. Therefore, buccal cells can serve as convenient sample sources to collect biomarkers associated with the risk of stunting. This study aims to describe the feasibility of nanopore adaptive sampling in detecting DNA methylation from children's buccal DNA. We used adaptive sampling of Oxford Nanopore Technology on barcoded samples to describe differential methylation associated with malnutrition. Overall, the level of 5-methylcytosine (5mC) was lower in stunted children than in normal children. We also found differentially methylated regions at the MIR6724 and RNA45SN1 gene loci on chromosome 21, which was higher in stunted children than in normal children. We described and detected differential DNA methylation in the locus previously not known to be associated with stunting. Interestingly, this locus on chromosome 21 has been implicated in the stunted phenotype of Down syndrome.

发育迟缓是慢性营养不良的结果,原因是在生命的最初 1000 天内缺乏表观遗传编程所需的微量元素甲基供体。利用血液 DNA 进行亚硫酸氢盐转化的甲基化研究具有侵入性,可能不适合大规模流行病学调查或营养干预计划。颊上皮甲基化可能反映了早期种系甲基化。因此,颊细胞可以作为方便的样本来源,收集与发育迟缓风险相关的生物标志物。本研究旨在描述纳米孔自适应采样检测儿童颊细胞DNA甲基化的可行性。我们利用牛津纳米孔技术对条形码样本进行自适应采样,以描述与营养不良相关的不同甲基化情况。总体而言,发育迟缓儿童的 5-甲基胞嘧啶(5mC)含量低于正常儿童。我们还在 21 号染色体上的 MIR6724 和 RNA45SN1 基因位点发现了不同的甲基化区域,发育迟缓儿童的甲基化水平高于正常儿童。我们描述并检测了以前不知道与发育迟缓有关的基因位点的不同 DNA 甲基化。有趣的是,21 号染色体上的这个基因座与唐氏综合征的发育迟缓表型有关。
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引用次数: 0
TET1 inhibits the migration and invasion of cervical cancer cells by regulating autophagy. TET1 通过调节自噬抑制宫颈癌细胞的迁移和侵袭。
IF 3.7 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-12-01 Epub Date: 2024-03-03 DOI: 10.1080/15592294.2024.2323751
Ji Ren, Xiuying Chen, Jing Li, Yuxin Zan, Shan Wang, Yujie Tan, Yan Ding

Methylation modifications play pertinent roles in regulating gene expression and various biological processes. The silencing of the demethylase enzyme TET1 can affect the expressions of key oncogenes or tumour suppressor genes, thus contributing to tumour formation. Nonetheless, how TET1 affects the progression of cervical cancer is yet to be elucidated. In this study, we found that the expression of TET1 was significantly downregulated in cervical cancer tissues. Functionally, TET1 knockdown in cervical cancer cells can promote cell proliferation, migration, invasion, cervical xenograft tumour formation and EMT. On the contrary, its overexpression can reverse the aforementioned processes. Moreover, the autophagy level of cervical cancer cells can be enhanced after TET1 knockdown. Mechanistically, methylated DNA immunoprecipitation (MeDIP)-sequencing and MeDIP quantitative real-time PCR revealed that TET1 mediates the methylation of autophagy promoter regions. These findings suggest that TET1 affects the autophagy of cervical cancer cells by altering the methylation levels of NKRF or HIST1H2AK, but the specific mechanism needs to be investigated further.

甲基化修饰在调节基因表达和各种生物过程中发挥着重要作用。去甲基化酶 TET1 的沉默会影响关键癌基因或肿瘤抑制基因的表达,从而导致肿瘤的形成。然而,TET1如何影响宫颈癌的进展尚待阐明。在这项研究中,我们发现 TET1 在宫颈癌组织中的表达明显下调。在功能上,TET1 在宫颈癌细胞中的敲除可促进细胞增殖、迁移、侵袭、宫颈异种移植瘤的形成和 EMT。相反,TET1 的过表达可以逆转上述过程。此外,TET1 基因敲除后,宫颈癌细胞的自噬水平也会提高。从机理上讲,甲基化DNA免疫沉淀(MeDIP)测序和MeDIP定量实时PCR发现,TET1介导了自噬启动子区域的甲基化。这些研究结果表明,TET1通过改变NKRF或HIST1H2AK的甲基化水平来影响宫颈癌细胞的自噬,但具体机制还有待进一步研究。
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引用次数: 0
History of exposure to copper influences transgenerational gene expression responses in Daphnia magna. 铜的暴露史影响大型蚤的基因表达反应。
IF 3.7 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-12-01 Epub Date: 2023-12-28 DOI: 10.1080/15592294.2023.2296275
Guilherme Jeremias, Ana-Belén Muñiz-González, Fernando José Mendes Gonçalves, José-Luis Martínez-Guitarte, Jana Asselman, Joana Luísa Pereira

The establishment of transgenerational effects following chemical exposure is a powerful phenomenon, capable of modulating ecosystem health beyond exposure periods. This study assessed the transgenerational effects occurring due to copper exposure in the invertebrate D. magna at the transcriptional level, while evaluating the role of exposure history on such responses. Thus, daphnids acclimated for several generations in a copper vs. clean medium were then exposed for one generation (F0) to this metal, and monitored for the following non-exposed generations (F1, F2 and F3). Organisms differing in exposure histories showed remarkably different transcriptional profiles at the F0, with naïve organisms being more profoundly affected. These trends were confirmed for F3 treatments, which presented different transcriptional patterns for genes involved in detoxification, oxidative stress, DNA damage repair, circadian clock functioning and epigenetic regulation. Furthermore, regardless of exposure history, a great number of histone modifier genes were always found transcriptionally altered, thus suggesting the involvement of histone modifications in the response of Daphnia to metal exposure. Lastly, remarkably distinct transgenerational transcriptional responses were found between naïve and non-naïve organisms, thereby highlighting the influence of exposure history on gene expression and confirming the capacity of metals to determine transgenerational transcriptional effects across non-exposed generations.

接触化学物质后产生的跨代效应是一种强大的现象,能够在接触期之后调节生态系统的健康。本研究在转录水平上评估了铜暴露对无脊椎动物大型蚤(D. magna)产生的跨代效应,同时评估了暴露历史对这种反应的作用。因此,在铜与清洁培养基中驯化了几代的水蚤,然后将其中一代(F0)暴露于这种金属,并对其后未暴露的几代(F1、F2 和 F3)进行监测。暴露历史不同的生物在 F0 代表现出明显不同的转录特征,天真生物受到的影响更大。这些趋势在 F3 处理中得到了证实,涉及解毒、氧化应激、DNA 损伤修复、昼夜节律钟功能和表观遗传调控的基因出现了不同的转录模式。此外,无论暴露历史如何,大量组蛋白修饰基因都发生了转录改变,这表明组蛋白修饰参与了水蚤对金属暴露的反应。最后,研究还发现,未受金属暴露的水蚤和未受金属暴露的水蚤之间存在明显不同的跨代转录反应,从而凸显了暴露历史对基因表达的影响,并证实了金属有能力决定非暴露代之间的跨代转录效应。
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引用次数: 0
Evaluating the utility of ZNF331 promoter methylation as a prognostic and predictive marker in stage III colon cancer: results from CALGB 89803 (Alliance). 评估 ZNF331 启动子甲基化作为 III 期结肠癌预后和预测标志物的效用:CALGB 89803(联盟)的研究结果。
IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-05-08 DOI: 10.1080/15592294.2024.2349980
Elizabeth S Nakasone, Tyler J Zemla, Ming Yu, She Yu Lin, Fang-Shu Ou, Kelly Carter, Federico Innocenti, Leonard Saltz, William M Grady, Stacey A Cohen

While epigenomic alterations are common in colorectal cancers (CRC), few epigenomic biomarkers that risk-stratify patients have been identified. We thus sought to determine the potential of ZNF331 promoter hypermethylation (mZNF331) as a prognostic and predictive marker in colon cancer. We examined the association of mZNF331 with clinicopathologic features, relapse, survival, and treatment efficacy in patients with stage III colon cancer treated within a randomized adjuvant chemotherapy trial (CALGB/Alliance89803). Residual tumour tissue was available for genomic DNA extraction and methylation analysis for 385 patients. ZNF331 promoter methylation status was determined by bisulphite conversion and fluorescence-based real-time polymerase chain reaction. Kaplan-Meier estimator and Cox proportional hazard models were used to assess the prognostic and predictive role of mZNF331 in this well-annotated dataset, adjusting for clinicopathologic features and standard molecular markers. mZNF331 was observed in 267/385 (69.4%) evaluable cases. Histopathologic features were largely similar between patients with mZNF331 compared to unmethylated ZNF331 (unmZNFF31). There was no significant difference in disease-free or overall survival between patients with mZNF331 versus unmZNF331 colon cancers, even when adjusting for clinicopathologic features and molecular marker status. Similarly, there was no difference in disease-free or overall survival across treatment arms when stratified by ZNF331 methylation status. While ZNF331 promoter hypermethylation is frequently observed in CRC, our current study of a small subset of patients with stage III colon cancer suggests limited applicability as a prognostic marker. Larger studies may provide more insight and clarity into the applicability of mZNF331 as a prognostic and predictive marker.

虽然表观基因组改变在结直肠癌(CRC)中很常见,但能对患者进行风险分层的表观基因组生物标志物却很少被发现。因此,我们试图确定 ZNF331 启动子高甲基化(mZNF331)作为结肠癌预后和预测标志物的潜力。我们研究了在随机辅助化疗试验(CALGB/Alliance89803)中接受治疗的 III 期结肠癌患者的 mZNF331 与临床病理特征、复发、生存和治疗效果的关系。385名患者的残留肿瘤组织可用于基因组DNA提取和甲基化分析。ZNF331启动子甲基化状态是通过亚硫酸氢盐转化和荧光实时聚合酶链反应确定的。采用 Kaplan-Meier 估计器和 Cox 比例危险模型来评估 mZNF331 在这一注释完备的数据集中的预后和预测作用,并对临床病理特征和标准分子标记进行调整。与未甲基化的 ZNF331(unmZNFF31)相比,mZNF331 患者的组织病理学特征基本相似。mZNF331与unmZNF331结肠癌患者的无病存活率或总存活率没有明显差异,即使对临床病理特征和分子标记状态进行调整也是如此。同样,根据 ZNF331 甲基化状态进行分层后,各治疗组的无病生存率或总生存率也没有差异。虽然 ZNF331 启动子高甲基化在 CRC 中经常被观察到,但我们目前对 III 期结肠癌患者中一小部分人的研究表明,ZNF331 作为预后标志物的适用性有限。更大规模的研究可能会让我们对 mZNF331 作为预后和预测标志物的适用性有更深入的了解和更清晰的认识。
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引用次数: 0
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Epigenetics
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