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The association between prenatal famine, DNA methylation and mental disorders: a systematic review and meta-analysis. 产前饥荒、DNA甲基化与精神障碍之间的关系:一项系统综述和荟萃分析。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-09-16 DOI: 10.1186/s13148-023-01557-y
Heike Eichenauer, Ulrike Ehlert

Background: Undernutrition in pregnant women is an unfavorable environmental condition that can affect the intrauterine development via epigenetic mechanisms and thus have long-lasting detrimental consequences for the mental health of the offspring later in life. One epigenetic mechanism that has been associated with mental disorders and undernutrition is alterations in DNA methylation. The effect of prenatal undernutrition on the mental health of adult offspring can be analyzed through quasi-experimental studies such as famine studies. The present systematic review and meta-analysis aims to analyze the association between prenatal famine exposure, DNA methylation, and mental disorders in adult offspring. We further investigate whether altered DNA methylation as a result of prenatal famine exposure is prospectively linked to mental disorders.

Methods: We conducted a systematic search of the databases PubMed and PsycINFO to identify relevant records up to September 2022 on offspring whose mothers experienced famine directly before and/or during pregnancy, examining the impact of prenatal famine exposure on the offspring's DNA methylation and/or mental disorders or symptoms.

Results: The systematic review showed that adults who were prenatally exposed to famine had an increased risk of schizophrenia and depression. Several studies reported an association between prenatal famine exposure and hyper- or hypomethylation of specific genes. The largest number of studies reported differences in DNA methylation of the IGF2 gene. Altered DNA methylation of the DUSP22 gene mediated the association between prenatal famine exposure and schizophrenia in adult offspring. Meta-analysis confirmed the increased risk of schizophrenia following prenatal famine exposure. For DNA methylation, meta-analysis was not suitable due to different microarrays/data processing approaches and/or unavailable data.

Conclusion: Prenatal famine exposure is associated with an increased risk of mental disorders and DNA methylation changes. The findings suggest that changes in DNA methylation of genes involved in neuronal, neuroendocrine, and immune processes may be a mechanism that promotes the development of mental disorders such as schizophrenia and depression in adult offspring. Such findings are crucial given that undernutrition has risen worldwide, increasing the risk of famine and thus also of negative effects on mental health.

背景:孕妇营养不足是一种不利的环境条件,可通过表观遗传学机制影响宫内发育,从而对后代日后的心理健康产生长期不利影响。一种与精神障碍和营养不良相关的表观遗传学机制是DNA甲基化的改变。产前营养不良对成年子女心理健康的影响可以通过饥荒研究等准实验研究来分析。本系统综述和荟萃分析旨在分析产前饥荒暴露、DNA甲基化和成年后代精神障碍之间的关系。我们进一步研究了产前饥荒暴露导致的DNA甲基化改变是否与精神障碍有前瞻性联系。方法:我们对PubMed和PsycINFO数据库进行了系统搜索,以确定截至2022年9月,母亲在怀孕前和/或怀孕期间直接经历饥荒的后代的相关记录,检查产前饥荒暴露对后代DNA甲基化和/或精神障碍或症状的影响。结果:系统综述显示,产前接触饥荒的成年人患精神分裂症和抑郁症的风险增加。几项研究报告了产前饥荒暴露与特定基因的高甲基化或低甲基化之间的联系。报道IGF2基因DNA甲基化差异的研究数量最多。DUSP22基因DNA甲基化的改变介导了成年后代产前饥荒暴露与精神分裂症之间的关系。荟萃分析证实产前饥荒暴露后精神分裂症的风险增加。对于DNA甲基化,由于微阵列/数据处理方法不同和/或数据不可用,荟萃分析不适用。结论:产前饥荒暴露与精神障碍和DNA甲基化变化的风险增加有关。研究结果表明,参与神经元、神经内分泌和免疫过程的基因DNA甲基化的变化可能是促进成年后代精神分裂症和抑郁症等精神障碍发展的机制。鉴于营养不良在全球范围内加剧,增加了饥荒的风险,从而也对心理健康产生了负面影响,这些发现至关重要。
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引用次数: 0
Evaluation of commercial kits for isolation and bisulfite conversion of circulating cell-free tumor DNA from blood. 用于从血液中分离和亚硫酸氢盐转化循环无细胞肿瘤DNA的商业试剂盒的评估。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-09-14 DOI: 10.1186/s13148-023-01563-0
Stine H Kresse, Sara Brandt-Winge, Heidi Pharo, Bjørnar T B Flatin, Marine Jeanmougin, Hege Marie Vedeld, Guro E Lind

Background: DNA methylation biomarkers in circulating cell-free DNA (cfDNA) have great clinical potential for cancer management. Most methods for DNA methylation analysis require bisulfite conversion, causing DNA degradation and loss. This is particularly challenging for cfDNA, which is naturally fragmented and normally present in low amounts. The aim of the present study was to identify an optimal combination of cfDNA isolation and bisulfite conversion kits for downstream analysis of DNA methylation biomarkers in plasma.

Results: Of the five tested bisulfite conversion kits (EpiJET Bisulfite Conversion Kit, EpiTect Plus DNA Bisulfite Kit (EpiTect), EZ DNA Methylation-Direct Kit, Imprint DNA Modification Kit (Imprint) and Premium Bisulfite Kit), the highest and lowest DNA yield and recovery were achieved using the EpiTect kit and the Imprint kit, respectively, with more than double the amount of DNA for the EpiTect kit. Of the three tested cfDNA isolation kits (Maxwell RSC ccfDNA Plasma Kit, QIAamp Circulating Nucleic Acid Kit (CNA) and QIAamp MinElute ccfDNA Mini Kit), the CNA kit yielded around twice as much cfDNA compared to the two others kits, although with more high molecular weight DNA present. When comparing various combinations of cfDNA isolation kits and bisulfite conversion kits, the CNA kit and the EpiTect kit were identified as the best-performing combination, resulting in the highest yield of bisulfite converted cfDNA from normal plasma, as measured by droplet digital PCR (ddPCR). As a proof of principle, this kit combination was used to process plasma samples from 13 colorectal cancer patients for subsequent ddPCR methylation analysis of BCAT1 and IKZF1. Methylation of BCAT1 and/or IKZF1 was identified in 6/10 (60%) stage IV patients and 1/3 (33%) stage III patients.

Conclusions: Based on a thorough evaluation of five bisulfite conversion kits and three cfDNA isolation kits, both individually and in combination, the CNA kit and the EpiTect kit were identified as the best-performing kit combination, with highest DNA yield and recovery across a range of DNA input amounts. The combination was successfully used for detection of clinically relevant DNA methylation biomarkers in plasma from cancer patients.

背景:循环无细胞DNA(cfDNA)中的DNA甲基化生物标志物在癌症治疗中具有巨大的临床潜力。大多数DNA甲基化分析方法都需要亚硫酸氢盐转化,从而导致DNA降解和丢失。这对cfDNA来说尤其具有挑战性,因为cfDNA是天然碎片化的,通常以少量存在。本研究的目的是确定cfDNA分离和亚硫酸氢盐转化试剂盒的最佳组合,用于血浆中DNA甲基化生物标志物的下游分析。结果:在五种测试的亚硫酸氢盐转化试剂盒(EpiJET亚硫酸氢转化试剂盒、EpiTect Plus DNA亚硫酸氢试剂盒(EpiTect)、EZ DNA甲基化直接试剂盒、印迹DNA修饰试剂盒(印迹)和高级亚硫酸氢化试剂盒)中,使用EpiTect试剂盒和印迹试剂盒分别获得了最高和最低的DNA产率和回收率,其DNA量是EpiTect试剂盒的两倍以上。在三种测试的cfDNA分离试剂盒(Maxwell RSC ccfDNA血浆试剂盒、QIAamp循环核酸试剂盒(CNA)和QIAamp MinElute ccfDNA迷你试剂盒)中,CNA试剂盒产生的cfDNA大约是其他两种试剂盒的两倍,尽管存在更多的高分子量DNA。当比较cfDNA分离试剂盒和亚硫酸氢盐转化试剂盒的各种组合时,CNA试剂盒和EpiTect试剂盒被确定为性能最佳的组合,通过液滴数字PCR(ddPCR)测量,从正常血浆中获得亚硫酸氢氢盐转化的cfDNA的产率最高。作为原理证明,该试剂盒组合用于处理13名癌症结直肠癌患者的血浆样本,用于随后对BCAT1和IKZF1进行ddPCR甲基化分析。在6/10(60%)的IV期患者和1/3(33%)的III期患者中发现BCAT1和/或IKZF1的甲基化。结论:根据对五个亚硫酸氢盐转化试剂盒和三个cfDNA分离试剂盒(单独和组合)的全面评估,CNA试剂盒和EpiTect试剂盒被确定为性能最佳的试剂盒组合,在一系列DNA输入量中具有最高的DNA产量和回收率。该组合成功用于检测癌症患者血浆中临床相关的DNA甲基化生物标志物。
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引用次数: 0
Crosstalk between DNA methylation and hypoxia in acute myeloid leukaemia. 急性髓细胞白血病中DNA甲基化与缺氧之间的串扰。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-09-13 DOI: 10.1186/s13148-023-01566-x
Sam Humphries, Danielle R Bond, Zacary P Germon, Simon Keely, Anoop K Enjeti, Matthew D Dun, Heather J Lee

Background: Acute myeloid leukaemia (AML) is a deadly disease characterised by the uncontrolled proliferation of immature myeloid cells within the bone marrow. Altered regulation of DNA methylation is an important epigenetic driver of AML, where the hypoxic bone marrow microenvironment can help facilitate leukaemogenesis. Thus, interactions between epigenetic regulation and hypoxia signalling will have important implications for AML development and treatment.

Main body: This review summarises the importance of DNA methylation and the hypoxic bone marrow microenvironment in the development, progression, and treatment of AML. Here, we focus on the role hypoxia plays on signalling and the subsequent regulation of DNA methylation. Hypoxia is likely to influence DNA methylation through altered metabolic pathways, transcriptional control of epigenetic regulators, and direct effects on the enzymatic activity of epigenetic modifiers. DNA methylation may also prevent activation of hypoxia-responsive genes, demonstrating bidirectional crosstalk between epigenetic regulation and the hypoxic microenvironment. Finally, we consider the clinical implications of these interactions, suggesting that reduced cell cycling within the hypoxic bone marrow may decrease the efficacy of hypomethylating agents.

Conclusion: Hypoxia is likely to influence AML progression through complex interactions with DNA methylation, where the therapeutic efficacy of hypomethylating agents may be limited within the hypoxic bone marrow. To achieve optimal outcomes for AML patients, future studies should therefore consider co-treatments that can promote cycling of AML cells within the bone marrow or encourage their dissociation from the bone marrow.

背景:急性髓细胞白血病(AML)是一种致命的疾病,其特征是骨髓中未成熟髓细胞的增殖失控。DNA甲基化调节的改变是AML的重要表观遗传学驱动因素,缺氧的骨髓微环境有助于促进白血病的发生。因此,表观遗传学调控和缺氧信号之间的相互作用将对AML的发展和治疗具有重要意义。正文:这篇综述总结了DNA甲基化和缺氧骨髓微环境在AML的发展、进展和治疗中的重要性。在这里,我们关注缺氧在信号传导和随后的DNA甲基化调控中所起的作用。缺氧可能通过改变代谢途径、表观遗传调控因子的转录控制以及对表观遗传修饰因子的酶活性的直接影响来影响DNA甲基化。DNA甲基化也可能阻止缺氧反应基因的激活,表明表观遗传调控和缺氧微环境之间存在双向串扰。最后,我们考虑了这些相互作用的临床意义,表明缺氧骨髓中细胞循环的减少可能会降低低甲基化药物的疗效。结论:缺氧可能通过与DNA甲基化的复杂相互作用影响AML的进展,其中低甲基化药物的治疗效果可能在缺氧的骨髓中受到限制。因此,为了实现AML患者的最佳结果,未来的研究应考虑联合治疗,以促进骨髓中AML细胞的循环或促进其从骨髓中分离。
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引用次数: 0
Low levels of circulating methylated IRX3 are related to worse outcome after transcatheter aortic valve implantation in patients with severe aortic stenosis. 严重主动脉狭窄患者经导管主动脉瓣植入术后,循环甲基化IRX3水平低与预后较差有关。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-09-11 DOI: 10.1186/s13148-023-01561-2
Leon Kanwischer, Xingbo Xu, Afifa Binta Saifuddin, Sabine Maamari, Xiaoying Tan, Fouzi Alnour, Björn Tampe, Thomas Meyer, Michael Zeisberg, Gerd Hasenfuss, Miriam Puls, Elisabeth M Zeisberg

Background: Aortic stenosis (AS) is one of the most common cardiac diseases and major cause of morbidity and mortality in the elderly. Transcatheter aortic valve implantation (TAVI) is performed in such patients with symptomatic severe AS and reduces mortality for the majority of these patients. However, a significant percentage dies within the first two years after TAVI, such that there is an interest to identify parameters, which predict outcome and could guide pre-TAVI patient selection. High levels of cardiac fibrosis have been identified as such independent predictor of cardiovascular mortality after TAVI. Promoter hypermethylation commonly leads to gene downregulation, and the Iroquois homeobox 3 (IRX3) gene was identified in a genome-wide transcriptome and methylome to be hypermethylated and downregulated in AS patients. In a well-described cohort of 100 TAVI patients in which cardiac fibrosis levels were quantified histologically in cardiac biopsies, and which had a follow-up of up to two years, we investigated if circulating methylated DNA of IRX3 in the peripheral blood is associated with cardiac fibrosis and/or mortality in AS patients undergoing TAVI and thus could serve as a biomarker to add information on outcome after TAVI.

Results: Patients with high levels of methylation in circulating IRX3 show a significantly increased survival as compared to patients with low levels of IRX3 methylation indicating that high peripheral IRX3 methylation is associated with an improved outcome. In the multivariable setting, peripheral IRX3 methylation acts as an independent predictor of all-cause mortality. While there is no significant correlation of levels of IRX3 methylation with cardiac death, there is a significant but very weak inverse correlation between circulating IRX3 promoter methylation level and the amount of cardiac fibrosis. Higher levels of peripheral IRX3 methylation further correlated with decreased cardiac IRX3 expression and vice versa.

Conclusions: High levels of IRX3 methylation in the blood of AS patients at the time of TAVI are associated with better overall survival after TAVI and at least partially reflect myocardial IRX3 expression. Circulating methylated IRX3 might aid as a potential biomarker to help guide both pre-TAVI patient selection and post-TAVI monitoring.

背景:主动脉狭窄(AS)是最常见的心脏病之一,也是老年人发病和死亡的主要原因。经导管主动脉瓣植入术(TAVI)适用于有症状的严重AS患者,可降低大多数患者的死亡率。然而,很大一部分人在TAVI后的头两年内死亡,因此有兴趣确定预测结果并指导TAVI前患者选择的参数。高水平的心脏纤维化已被确定为TAVI后心血管死亡率的独立预测因素。启动子超甲基化通常导致基因下调,易洛魁人同源框3(IRX3)基因在全基因组转录组和甲基组中被鉴定为在AS患者中超甲基化和下调。在一个由100名TAVI患者组成的队列中,心脏纤维化水平在心脏活检中进行了组织学量化,并进行了长达两年的随访,我们研究了外周血中IRX3的循环甲基化DNA是否与接受TAVI的AS患者的心脏纤维化和/或死亡率相关,从而可以作为一种生物标志物来增加TAVI后的结果信息。结果:与低水平IRX3的患者相比,循环IRX3中甲基化水平高的患者显示出显著提高的生存率甲基化表明高外周IRX3甲基化与改善的结果相关。在多变量环境中,外周IRX3甲基化是全因死亡率的独立预测因子。虽然IRX3甲基化水平与心脏死亡没有显著相关性,但循环IRX3启动子甲基化水平和心脏纤维化程度之间存在显著但非常弱的负相关性。外周IRX3甲基化水平的升高进一步与心脏IRX3表达的降低相关,反之亦然。结论:TAVI时AS患者血液中高水平的IRX3甲基化与TAVI后更好的总生存率相关,并且至少部分反映了心肌IRX3的表达。循环甲基化IRX3可能有助于作为一种潜在的生物标志物,帮助指导TAVI前患者的选择和TAVI后的监测。
{"title":"Low levels of circulating methylated IRX3 are related to worse outcome after transcatheter aortic valve implantation in patients with severe aortic stenosis.","authors":"Leon Kanwischer, Xingbo Xu, Afifa Binta Saifuddin, Sabine Maamari, Xiaoying Tan, Fouzi Alnour, Björn Tampe, Thomas Meyer, Michael Zeisberg, Gerd Hasenfuss, Miriam Puls, Elisabeth M Zeisberg","doi":"10.1186/s13148-023-01561-2","DOIUrl":"10.1186/s13148-023-01561-2","url":null,"abstract":"<p><strong>Background: </strong>Aortic stenosis (AS) is one of the most common cardiac diseases and major cause of morbidity and mortality in the elderly. Transcatheter aortic valve implantation (TAVI) is performed in such patients with symptomatic severe AS and reduces mortality for the majority of these patients. However, a significant percentage dies within the first two years after TAVI, such that there is an interest to identify parameters, which predict outcome and could guide pre-TAVI patient selection. High levels of cardiac fibrosis have been identified as such independent predictor of cardiovascular mortality after TAVI. Promoter hypermethylation commonly leads to gene downregulation, and the Iroquois homeobox 3 (IRX3) gene was identified in a genome-wide transcriptome and methylome to be hypermethylated and downregulated in AS patients. In a well-described cohort of 100 TAVI patients in which cardiac fibrosis levels were quantified histologically in cardiac biopsies, and which had a follow-up of up to two years, we investigated if circulating methylated DNA of IRX3 in the peripheral blood is associated with cardiac fibrosis and/or mortality in AS patients undergoing TAVI and thus could serve as a biomarker to add information on outcome after TAVI.</p><p><strong>Results: </strong>Patients with high levels of methylation in circulating IRX3 show a significantly increased survival as compared to patients with low levels of IRX3 methylation indicating that high peripheral IRX3 methylation is associated with an improved outcome. In the multivariable setting, peripheral IRX3 methylation acts as an independent predictor of all-cause mortality. While there is no significant correlation of levels of IRX3 methylation with cardiac death, there is a significant but very weak inverse correlation between circulating IRX3 promoter methylation level and the amount of cardiac fibrosis. Higher levels of peripheral IRX3 methylation further correlated with decreased cardiac IRX3 expression and vice versa.</p><p><strong>Conclusions: </strong>High levels of IRX3 methylation in the blood of AS patients at the time of TAVI are associated with better overall survival after TAVI and at least partially reflect myocardial IRX3 expression. Circulating methylated IRX3 might aid as a potential biomarker to help guide both pre-TAVI patient selection and post-TAVI monitoring.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"149"},"PeriodicalIF":5.7,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10496273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10306236","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
Unlocking the potential of targeting histone-modifying enzymes for treating IBD and CRC. 释放靶向组蛋白修饰酶治疗IBD和CRC的潜力。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-09-11 DOI: 10.1186/s13148-023-01562-1
Bing Liang, Yanhong Wang, Jiazhen Xu, Yingchun Shao, Dongming Xing

Dysregulation of histone modifications has been implicated in the pathogenesis of both inflammatory bowel disease (IBD) and colorectal cancer (CRC). These diseases are characterized by chronic inflammation, and alterations in histone modifications have been linked to their development and progression. Furthermore, the gut microbiota plays a crucial role in regulating immune responses and maintaining gut homeostasis, and it has been shown to exert effects on histone modifications and gene expression in host cells. Recent advances in our understanding of the roles of histone-modifying enzymes and their associated chromatin modifications in IBD and CRC have provided new insights into potential therapeutic interventions. In particular, inhibitors of histone-modifying enzymes have been explored in clinical trials as a possible therapeutic approach for these diseases. This review aims to explore these potential therapeutic interventions and analyze previous and ongoing clinical trials that examined the use of histone-modifying enzyme inhibitors for the treatment of IBD and CRC. This paper will contribute to the current body of knowledge by exploring the latest advances in the field and discussing the limitations of existing approaches. By providing a comprehensive analysis of the potential benefits of targeting histone-modifying enzymes for the treatment of IBD and CRC, this review will help to inform future research in this area and highlight the significance of understanding the functions of histone-modifying enzymes and their associated chromatin modifications in gastrointestinal disorders for the development of potential therapeutic interventions.

组蛋白修饰的失调与炎症性肠病(IBD)和癌症(CRC)的发病机制有关。这些疾病的特点是慢性炎症,组蛋白修饰的改变与它们的发展和进展有关。此外,肠道微生物群在调节免疫反应和维持肠道稳态方面发挥着至关重要的作用,并已被证明对宿主细胞中的组蛋白修饰和基因表达产生影响。最近,我们对组蛋白修饰酶及其相关染色质修饰在IBD和CRC中的作用的理解取得了进展,为潜在的治疗干预措施提供了新的见解。特别是,组蛋白修饰酶抑制剂已在临床试验中被探索为治疗这些疾病的可能方法。这篇综述旨在探索这些潜在的治疗干预措施,并分析先前和正在进行的临床试验,这些试验检查了组蛋白修饰酶抑制剂用于治疗IBD和CRC。本文将通过探索该领域的最新进展和讨论现有方法的局限性,为当前的知识体系做出贡献。通过对靶向组蛋白修饰酶治疗IBD和CRC的潜在益处进行全面分析,这篇综述将有助于为该领域的未来研究提供信息,并强调了解组蛋白修饰酶及其相关染色质修饰在胃肠道疾病中的作用对开发潜在的治疗干预措施的重要性。
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引用次数: 0
Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude. 对出生时和儿童期DNA甲基化的分析揭示了与出生季节和纬度相关的变化。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-09-11 DOI: 10.1186/s13148-023-01542-5
Latha Kadalayil, Md Zahangir Alam, Cory Haley White, Akram Ghantous, Esther Walton, Olena Gruzieva, Simon Kebede Merid, Ashish Kumar, Ritu P Roy, Olivia Solomon, Karen Huen, Brenda Eskenazi, Peter Rzehak, Veit Grote, Jean-Paul Langhendries, Elvira Verduci, Natalia Ferre, Darek Gruszfeld, Lu Gao, Weihua Guan, Xuehuo Zeng, Enrique F Schisterman, John F Dou, Kelly M Bakulski, Jason I Feinberg, Munawar Hussain Soomro, Giancarlo Pesce, Nour Baiz, Elena Isaevska, Michelle Plusquin, Marina Vafeiadi, Theano Roumeliotaki, Sabine A S Langie, Arnout Standaert, Catherine Allard, Patrice Perron, Luigi Bouchard, Evelien R van Meel, Janine F Felix, Vincent W V Jaddoe, Paul D Yousefi, Cecilia H Ramlau-Hansen, Caroline L Relton, Elmar W Tobi, Anne P Starling, Ivana V Yang, Maria Llambrich, Gillian Santorelli, Johanna Lepeule, Lucas A Salas, Mariona Bustamante, Susan L Ewart, Hongmei Zhang, Wilfried Karmaus, Stefan Röder, Ana Claudia Zenclussen, Jianping Jin, Wenche Nystad, Christian M Page, Maria Magnus, Dereje D Jima, Cathrine Hoyo, Rachel L Maguire, Tuomas Kvist, Darina Czamara, Katri Räikkönen, Tong Gong, Vilhelmina Ullemar, Sheryl L Rifas-Shiman, Emily Oken, Catarina Almqvist, Robert Karlsson, Jari Lahti, Susan K Murphy, Siri E Håberg, Stephanie London, Gunda Herberth, Hasan Arshad, Jordi Sunyer, Regina Grazuleviciene, Dana Dabelea, Régine P M Steegers-Theunissen, Ellen A Nohr, Thorkild I A Sørensen, Liesbeth Duijts, Marie-France Hivert, Vera Nelen, Maja Popovic, Manolis Kogevinas, Tim S Nawrot, Zdenko Herceg, Isabella Annesi-Maesano, M Daniele Fallin, Edwina Yeung, Carrie V Breton, Berthold Koletzko, Nina Holland, Joseph L Wiemels, Erik Melén, Gemma C Sharp, Matt J Silver, Faisal I Rezwan, John W Holloway

Background: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear.

Methods: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points.

Results: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N).

Conclusions: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.

背景:出生或妊娠期间环境暴露的季节性变化与许多成年特征和日后的健康结果有关。DNA甲基化(DNAm)是否在出生季节和终身表型之间的分子机制中发挥作用尚不清楚。方法:我们在妊娠和儿童表观遗传学联盟中进行了表观基因组范围的荟萃分析,以确定DNAm与出生季节的相关性,包括差异甲基化探针(DMPs)和区域(DMRs)。在两个时间点检查了相关性:出生时(21个队列,N = 9358)和1-11岁的儿童(12个队列,N = 3610)。我们进行了荟萃分析,以评估纬度对两个时间点出生季节特定关联的影响。结果:我们确定了出生季节和DNAm之间的相关性(错误发现率调整p值 结论:在这项大规模的表观基因组荟萃分析研究中,我们为(i)DNAm和出生季节之间的关联提供了证据,这种关联在一年中的季节中是独特的(时间效应),以及(ii)季节关联的纬度依赖性变化(空间效应)。DNAm可能在出生季节对成人健康结果影响的分子机制中发挥作用。
{"title":"Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude.","authors":"Latha Kadalayil, Md Zahangir Alam, Cory Haley White, Akram Ghantous, Esther Walton, Olena Gruzieva, Simon Kebede Merid, Ashish Kumar, Ritu P Roy, Olivia Solomon, Karen Huen, Brenda Eskenazi, Peter Rzehak, Veit Grote, Jean-Paul Langhendries, Elvira Verduci, Natalia Ferre, Darek Gruszfeld, Lu Gao, Weihua Guan, Xuehuo Zeng, Enrique F Schisterman, John F Dou, Kelly M Bakulski, Jason I Feinberg, Munawar Hussain Soomro, Giancarlo Pesce, Nour Baiz, Elena Isaevska, Michelle Plusquin, Marina Vafeiadi, Theano Roumeliotaki, Sabine A S Langie, Arnout Standaert, Catherine Allard, Patrice Perron, Luigi Bouchard, Evelien R van Meel, Janine F Felix, Vincent W V Jaddoe, Paul D Yousefi, Cecilia H Ramlau-Hansen, Caroline L Relton, Elmar W Tobi, Anne P Starling, Ivana V Yang, Maria Llambrich, Gillian Santorelli, Johanna Lepeule, Lucas A Salas, Mariona Bustamante, Susan L Ewart, Hongmei Zhang, Wilfried Karmaus, Stefan Röder, Ana Claudia Zenclussen, Jianping Jin, Wenche Nystad, Christian M Page, Maria Magnus, Dereje D Jima, Cathrine Hoyo, Rachel L Maguire, Tuomas Kvist, Darina Czamara, Katri Räikkönen, Tong Gong, Vilhelmina Ullemar, Sheryl L Rifas-Shiman, Emily Oken, Catarina Almqvist, Robert Karlsson, Jari Lahti, Susan K Murphy, Siri E Håberg, Stephanie London, Gunda Herberth, Hasan Arshad, Jordi Sunyer, Regina Grazuleviciene, Dana Dabelea, Régine P M Steegers-Theunissen, Ellen A Nohr, Thorkild I A Sørensen, Liesbeth Duijts, Marie-France Hivert, Vera Nelen, Maja Popovic, Manolis Kogevinas, Tim S Nawrot, Zdenko Herceg, Isabella Annesi-Maesano, M Daniele Fallin, Edwina Yeung, Carrie V Breton, Berthold Koletzko, Nina Holland, Joseph L Wiemels, Erik Melén, Gemma C Sharp, Matt J Silver, Faisal I Rezwan, John W Holloway","doi":"10.1186/s13148-023-01542-5","DOIUrl":"10.1186/s13148-023-01542-5","url":null,"abstract":"<p><strong>Background: </strong>Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear.</p><p><strong>Methods: </strong>We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points.</p><p><strong>Results: </strong>We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N).</p><p><strong>Conclusions: </strong>In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"148"},"PeriodicalIF":5.7,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10496224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10231551","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
Degradation of methylation signals in cryopreserved DNA. 冷冻保存DNA中甲基化信号的降解。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-09-11 DOI: 10.1186/s13148-023-01565-y
Ning Yuan Lee, Melissa Hum, Guek Peng Tan, Ai Choo Seah, Patricia T Kin, Ngiap Chuan Tan, Hai-Yang Law, Ann S G Lee

Background: Blood-based DNA methylation has shown great promise as a biomarker in a wide variety of diseases. Studies of DNA methylation in blood often utilize samples which have been cryopreserved for years or even decades. Therefore, changes in DNA methylation associated with long-term cryopreservation can introduce biases or otherwise mislead methylation analyses of cryopreserved DNA. However, previous studies have presented conflicting results with studies reporting hypomethylation, no effect, or even hypermethylation of DNA following long-term cryopreservation. These studies may have been limited by insufficient sample sizes, or by their profiling of methylation only on an aggregate global scale, or profiling of only a few CpGs.

Results: We analyzed two large prospective cohorts: a discovery (n = 126) and a validation (n = 136) cohort, where DNA was cryopreserved for up to four years. In both cohorts there was no detectable change in mean global methylation across increasing storage durations as DNA. However, when analysis was performed on the level of individual CpG methylation both cohorts exhibited a greater number of hypomethylated than hypermethylated CpGs at q-value < 0.05 (4049 hypomethylated but only 50 hypermethylated CpGs in discovery, and 63 hypomethylated but only 6 hypermethylated CpGs in validation). The results were the same even after controlling for age, storage duration as buffy coat prior to DNA extraction, and estimated cell type composition. Furthermore, we find that in both cohorts, CpGs have a greater likelihood to be hypomethylated the closer they are to a CpG island; except for CpGs at the CpG islands themselves which are less likely to be hypomethylated.

Conclusion: Cryopreservation of DNA after a few years results in a detectable bias toward hypomethylation at the level of individual CpG methylation, though when analyzed in aggregate there is no detectable change in mean global methylation. Studies profiling methylation in cryopreserved DNA should be mindful of this hypomethylation bias, and more attention should be directed at developing more stable methods of DNA cryopreservation for biomedical research or clinical use.

背景:基于血液的DNA甲基化作为一种生物标志物在多种疾病中显示出巨大的前景。血液中DNA甲基化的研究通常使用冷冻保存数年甚至数十年的样本。因此,与长期冷冻保存相关的DNA甲基化的变化可能会引入偏见或以其他方式误导冷冻保存DNA的甲基化分析。然而,先前的研究结果与报告长期冷冻保存后DNA低甲基化、无作用甚至高甲基化的研究结果相矛盾。这些研究可能受到样本量不足的限制,或者仅在总体范围内对甲基化进行分析,或者仅对少数CpG进行分析。结果:我们分析了两个大型前瞻性队列: = 126)和验证(n = 136)队列,其中DNA被冷冻保存长达四年。在这两个队列中,随着DNA储存时间的增加,平均全局甲基化没有可检测的变化。然而,当对单个CpG甲基化水平进行分析时,在q值下,两个队列都表现出比高甲基化CpG更多的低甲基化CpGs 结论:几年后DNA的冷冻保存导致在单个CpG甲基化水平上对低甲基化的可检测的偏向,尽管在总体分析时,平均全局甲基化没有可检测的变化。分析冷冻保存DNA中甲基化的研究应注意这种低甲基化倾向,并应更多地关注开发更稳定的DNA冷冻保存方法,用于生物医学研究或临床应用。
{"title":"Degradation of methylation signals in cryopreserved DNA.","authors":"Ning Yuan Lee, Melissa Hum, Guek Peng Tan, Ai Choo Seah, Patricia T Kin, Ngiap Chuan Tan, Hai-Yang Law, Ann S G Lee","doi":"10.1186/s13148-023-01565-y","DOIUrl":"10.1186/s13148-023-01565-y","url":null,"abstract":"<p><strong>Background: </strong>Blood-based DNA methylation has shown great promise as a biomarker in a wide variety of diseases. Studies of DNA methylation in blood often utilize samples which have been cryopreserved for years or even decades. Therefore, changes in DNA methylation associated with long-term cryopreservation can introduce biases or otherwise mislead methylation analyses of cryopreserved DNA. However, previous studies have presented conflicting results with studies reporting hypomethylation, no effect, or even hypermethylation of DNA following long-term cryopreservation. These studies may have been limited by insufficient sample sizes, or by their profiling of methylation only on an aggregate global scale, or profiling of only a few CpGs.</p><p><strong>Results: </strong>We analyzed two large prospective cohorts: a discovery (n = 126) and a validation (n = 136) cohort, where DNA was cryopreserved for up to four years. In both cohorts there was no detectable change in mean global methylation across increasing storage durations as DNA. However, when analysis was performed on the level of individual CpG methylation both cohorts exhibited a greater number of hypomethylated than hypermethylated CpGs at q-value < 0.05 (4049 hypomethylated but only 50 hypermethylated CpGs in discovery, and 63 hypomethylated but only 6 hypermethylated CpGs in validation). The results were the same even after controlling for age, storage duration as buffy coat prior to DNA extraction, and estimated cell type composition. Furthermore, we find that in both cohorts, CpGs have a greater likelihood to be hypomethylated the closer they are to a CpG island; except for CpGs at the CpG islands themselves which are less likely to be hypomethylated.</p><p><strong>Conclusion: </strong>Cryopreservation of DNA after a few years results in a detectable bias toward hypomethylation at the level of individual CpG methylation, though when analyzed in aggregate there is no detectable change in mean global methylation. Studies profiling methylation in cryopreserved DNA should be mindful of this hypomethylation bias, and more attention should be directed at developing more stable methods of DNA cryopreservation for biomedical research or clinical use.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"147"},"PeriodicalIF":5.7,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10496221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10240123","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
A quantum physics layer of epigenetics: a hypothesis deduced from charge transfer and chirality-induced spin selectivity of DNA. 表观遗传学的量子物理层:从DNA的电荷转移和手性诱导的自旋选择性推断出的假说。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-09-08 DOI: 10.1186/s13148-023-01560-3
Reiner Siebert, Ole Ammerpohl, Mirko Rossini, Dennis Herb, Sven Rau, Martin B Plenio, Fedor Jelezko, Joachim Ankerhold

Background: Epigenetic mechanisms are informational cellular processes instructing normal and diseased phenotypes. They are associated with DNA but without altering the DNA sequence. Whereas chemical processes like DNA methylation or histone modifications are well-accepted epigenetic mechanisms, we herein propose the existence of an additional quantum physics layer of epigenetics.

Results: We base our hypothesis on theoretical and experimental studies showing quantum phenomena to be active in double-stranded DNA, even under ambient conditions. These phenomena include coherent charge transfer along overlapping pi-orbitals of DNA bases and chirality-induced spin selectivity. Charge transfer via quantum tunneling mediated by overlapping orbitals results in charge delocalization along several neighboring bases, which can even be extended by classical (non-quantum) electron hopping. Such charge transfer is interrupted by flipping base(s) out of the double-strand e.g., by DNA modifying enzymes. Charge delocalization can directly alter DNA recognition by proteins or indirectly by DNA structural changes e.g., kinking. Regarding sequence dependency, charge localization, shown to favor guanines, could influence or even direct epigenetic changes, e.g., modification of cytosines in CpG dinucleotides. Chirality-induced spin selectivity filters electrons for their spin along DNA and, thus, is not only an indicator for quantum coherence but can potentially affect DNA binding properties.

Conclusions: Quantum effects in DNA are prone to triggering and manipulation by external means. By the hypothesis put forward here, we would like to foster research on "Quantum Epigenetics" at the interface of medicine, biology, biochemistry, and physics to investigate the potential epigenetic impact of quantum physical principles on (human) life.

背景:表观遗传学机制是指示正常和患病表型的信息细胞过程。它们与DNA相关,但不会改变DNA序列。尽管DNA甲基化或组蛋白修饰等化学过程是公认的表观遗传学机制,但我们在这里提出了表观遗传学的额外量子物理层的存在。结果:我们的假设建立在理论和实验研究的基础上,这些研究表明,即使在环境条件下,双链DNA中的量子现象也很活跃。这些现象包括沿着DNA碱基的重叠π轨道的相干电荷转移和手性诱导的自旋选择性。通过重叠轨道介导的量子隧穿进行的电荷转移导致电荷沿几个相邻碱基的离域,这甚至可以通过经典(非量子)电子跳跃来扩展。这种电荷转移通过将碱基从双链中翻转出来而中断,例如通过DNA修饰酶。电荷离域可以直接改变蛋白质对DNA的识别,或者通过DNA结构变化(例如扭结)间接改变。关于序列依赖性,显示有利于鸟嘌呤的电荷定位可能影响甚至指导表观遗传学变化,例如CpG二核苷酸中胞嘧啶的修饰。手性诱导的自旋选择性过滤了电子沿DNA的自旋,因此,它不仅是量子相干性的指标,而且可能影响DNA的结合特性。结论:DNA中的量子效应容易被外部手段触发和操纵。根据这里提出的假设,我们希望在医学、生物学、生物化学和物理学的界面上促进对“量子表观遗传学”的研究,以研究量子物理原理对(人类)生命的潜在表观遗传学影响。
{"title":"A quantum physics layer of epigenetics: a hypothesis deduced from charge transfer and chirality-induced spin selectivity of DNA.","authors":"Reiner Siebert, Ole Ammerpohl, Mirko Rossini, Dennis Herb, Sven Rau, Martin B Plenio, Fedor Jelezko, Joachim Ankerhold","doi":"10.1186/s13148-023-01560-3","DOIUrl":"10.1186/s13148-023-01560-3","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic mechanisms are informational cellular processes instructing normal and diseased phenotypes. They are associated with DNA but without altering the DNA sequence. Whereas chemical processes like DNA methylation or histone modifications are well-accepted epigenetic mechanisms, we herein propose the existence of an additional quantum physics layer of epigenetics.</p><p><strong>Results: </strong>We base our hypothesis on theoretical and experimental studies showing quantum phenomena to be active in double-stranded DNA, even under ambient conditions. These phenomena include coherent charge transfer along overlapping pi-orbitals of DNA bases and chirality-induced spin selectivity. Charge transfer via quantum tunneling mediated by overlapping orbitals results in charge delocalization along several neighboring bases, which can even be extended by classical (non-quantum) electron hopping. Such charge transfer is interrupted by flipping base(s) out of the double-strand e.g., by DNA modifying enzymes. Charge delocalization can directly alter DNA recognition by proteins or indirectly by DNA structural changes e.g., kinking. Regarding sequence dependency, charge localization, shown to favor guanines, could influence or even direct epigenetic changes, e.g., modification of cytosines in CpG dinucleotides. Chirality-induced spin selectivity filters electrons for their spin along DNA and, thus, is not only an indicator for quantum coherence but can potentially affect DNA binding properties.</p><p><strong>Conclusions: </strong>Quantum effects in DNA are prone to triggering and manipulation by external means. By the hypothesis put forward here, we would like to foster research on \"Quantum Epigenetics\" at the interface of medicine, biology, biochemistry, and physics to investigate the potential epigenetic impact of quantum physical principles on (human) life.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"145"},"PeriodicalIF":5.7,"publicationDate":"2023-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10492394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10208599","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
Altered H3K4me3 profile at the TFAM promoter causes mitochondrial alterations in preadipocytes from first-degree relatives of type 2 diabetics. TFAM启动子的H3K4me3图谱改变导致2型糖尿病一级亲属前脂肪细胞的线粒体改变。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-09-07 DOI: 10.1186/s13148-023-01556-z
Michele Longo, Federica Zatterale, Rosa Spinelli, Jamal Naderi, Luca Parrillo, Pasqualina Florese, Cecilia Nigro, Alessia Leone, Augusta Moccia, Antonella Desiderio, Gregory A Raciti, Claudia Miele, Ulf Smith, Francesco Beguinot

Background: First-degree relatives of type 2 diabetics (FDR) exhibit a high risk of developing type 2 diabetes (T2D) and feature subcutaneous adipocyte hypertrophy, independent of obesity. In FDR, adipose cell abnormalities contribute to early insulin-resistance and are determined by adipocyte precursor cells (APCs) early senescence and impaired recruitment into the adipogenic pathway. Epigenetic mechanisms signal adipocyte differentiation, leading us to hypothesize that abnormal epigenetic modifications cause adipocyte dysfunction and enhance T2D risk. To test this hypothesis, we examined the genome-wide histone profile in APCs from the subcutaneous adipose tissue of healthy FDR.

Results: Sequencing-data analysis revealed 2644 regions differentially enriched in lysine 4 tri-methylated H3-histone (H3K4me3) in FDR compared to controls (CTRL) with significant enrichment in mitochondrial-related genes. These included TFAM, which regulates mitochondrial DNA (mtDNA) content and stability. In FDR APCs, a significant reduction in H3K4me3 abundance at the TFAM promoter was accompanied by a reduction in TFAM mRNA and protein levels. FDR APCs also exhibited reduced mtDNA content and mitochondrial-genome transcription. In parallel, FDR APCs exhibited impaired differentiation and TFAM induction during adipogenesis. In CTRL APCs, TFAM-siRNA reduced mtDNA content, mitochondrial transcription and adipocyte differentiation in parallel with upregulation of the CDKN1A and ZMAT3 senescence genes. Furthermore, TFAM-siRNA significantly expanded hydrogen peroxide (H2O2)-induced senescence, while H2O2 did not affect TFAM expression.

Conclusions: Histone modifications regulate APCs ability to differentiate in mature cells, at least in part by modulating TFAM expression and affecting mitochondrial function. Reduced H3K4me3 enrichment at the TFAM promoter renders human APCs senescent and dysfunctional, increasing T2D risk.

背景:2型糖尿病患者(FDR)的一级亲属患2型糖尿病(T2D)的风险很高,其皮下脂肪细胞肥大与肥胖无关。在FDR中,脂肪细胞异常导致早期胰岛素抵抗,并由脂肪细胞前体细胞(APC)早衰和脂肪生成途径募集受损决定。表观遗传学机制是脂肪细胞分化的信号,使我们假设异常的表观遗传学修饰会导致脂肪细胞功能障碍并增加T2D风险。为了验证这一假设,我们检测了健康FDR皮下脂肪组织APC中的全基因组组蛋白图谱。结果:测序数据分析显示,与线粒体相关基因显著富集的对照组(CTRL)相比,FDR中2644个区域的赖氨酸4三甲基化H3组蛋白(H3K4me3)差异富集。其中包括调节线粒体DNA(mtDNA)含量和稳定性的TFAM。在FDR-APC中,TFAM启动子处H3K4me3丰度的显著降低伴随着TFAM mRNA和蛋白质水平的降低。FDR-APC还表现出线粒体DNA含量和线粒体基因组转录的降低。同时,FDR-APC在脂肪生成过程中表现出分化受损和TFAM诱导。在CTRL APC中,TFAM siRNA降低mtDNA含量、线粒体转录和脂肪细胞分化,同时上调CDKN1A和ZMAT3衰老基因。此外,TFAM siRNA显著扩大了过氧化氢(H2O2)诱导的衰老,而H2O2不影响TFAM的表达。结论:组蛋白修饰调节APC在成熟细胞中的分化能力,至少部分是通过调节TFAM的表达和影响线粒体功能。TFAM启动子处H3K4me3富集减少会使人APC衰老和功能失调,增加T2D风险。
{"title":"Altered H3K4me3 profile at the TFAM promoter causes mitochondrial alterations in preadipocytes from first-degree relatives of type 2 diabetics.","authors":"Michele Longo, Federica Zatterale, Rosa Spinelli, Jamal Naderi, Luca Parrillo, Pasqualina Florese, Cecilia Nigro, Alessia Leone, Augusta Moccia, Antonella Desiderio, Gregory A Raciti, Claudia Miele, Ulf Smith, Francesco Beguinot","doi":"10.1186/s13148-023-01556-z","DOIUrl":"10.1186/s13148-023-01556-z","url":null,"abstract":"<p><strong>Background: </strong>First-degree relatives of type 2 diabetics (FDR) exhibit a high risk of developing type 2 diabetes (T2D) and feature subcutaneous adipocyte hypertrophy, independent of obesity. In FDR, adipose cell abnormalities contribute to early insulin-resistance and are determined by adipocyte precursor cells (APCs) early senescence and impaired recruitment into the adipogenic pathway. Epigenetic mechanisms signal adipocyte differentiation, leading us to hypothesize that abnormal epigenetic modifications cause adipocyte dysfunction and enhance T2D risk. To test this hypothesis, we examined the genome-wide histone profile in APCs from the subcutaneous adipose tissue of healthy FDR.</p><p><strong>Results: </strong>Sequencing-data analysis revealed 2644 regions differentially enriched in lysine 4 tri-methylated H3-histone (H3K4me3) in FDR compared to controls (CTRL) with significant enrichment in mitochondrial-related genes. These included TFAM, which regulates mitochondrial DNA (mtDNA) content and stability. In FDR APCs, a significant reduction in H3K4me3 abundance at the TFAM promoter was accompanied by a reduction in TFAM mRNA and protein levels. FDR APCs also exhibited reduced mtDNA content and mitochondrial-genome transcription. In parallel, FDR APCs exhibited impaired differentiation and TFAM induction during adipogenesis. In CTRL APCs, TFAM-siRNA reduced mtDNA content, mitochondrial transcription and adipocyte differentiation in parallel with upregulation of the CDKN1A and ZMAT3 senescence genes. Furthermore, TFAM-siRNA significantly expanded hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>)-induced senescence, while H<sub>2</sub>O<sub>2</sub> did not affect TFAM expression.</p><p><strong>Conclusions: </strong>Histone modifications regulate APCs ability to differentiate in mature cells, at least in part by modulating TFAM expression and affecting mitochondrial function. Reduced H3K4me3 enrichment at the TFAM promoter renders human APCs senescent and dysfunctional, increasing T2D risk.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"144"},"PeriodicalIF":5.7,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10486065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10567276","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: Long-term environmental metal exposure is associated with hypomethylation of CpG sites in NFKB1 and other genes related to oncogenesis. 更正: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 : 2023-09-05 DOI: 10.1186/s13148-023-01559-w
Ani Stepanyan, Anna Petrackova, Siras Hakobyan, Jakub Savara, Suren Davitavyan, Eva Kriegova, Arsen Arakelyan
{"title":"Correction: Long-term environmental metal exposure is associated with hypomethylation of CpG sites in NFKB1 and other genes related to oncogenesis.","authors":"Ani Stepanyan, Anna Petrackova, Siras Hakobyan, Jakub Savara, Suren Davitavyan, Eva Kriegova, Arsen Arakelyan","doi":"10.1186/s13148-023-01559-w","DOIUrl":"10.1186/s13148-023-01559-w","url":null,"abstract":"","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"143"},"PeriodicalIF":5.7,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10478175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10180819","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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