首页 > 最新文献

Clinical Epigenetics最新文献

英文 中文
Histone lysine methyltransferase SMYD3 promotes oral squamous cell carcinoma tumorigenesis via H3K4me3-mediated HMGA2 transcription. 组蛋白赖氨酸甲基转移酶SMYD3通过h3k4me3介导的HMGA2转录促进口腔鳞状细胞癌的发生。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-26 DOI: 10.1186/s13148-023-01506-9
Zongcheng Yang, Fen Liu, Zongkai Li, Nianping Liu, Xinfeng Yao, Yu Zhou, Liyu Zhang, Pan Jiang, Honghong Liu, Lingming Kong, Chuandong Lang, Xin Xu, Jihui Jia, Takahito Nakajima, Wenchao Gu, Lixin Zheng, Zhihong Zhang

Background: Epigenetic dysregulation is essential to the tumorigenesis of oral squamous cell carcinoma (OSCC). SET and MYND domain-containing protein 3 (SMYD3), a histone lysine methyltransferase, is implicated in gene transcription regulation and tumor development. However, the roles of SMYD3 in OSCC initiation are not fully understood. The present study investigated the biological functions and mechanisms involved in the SMYD3-mediated tumorigenesis of OSCC utilizing bioinformatic approaches and validation assays with the aim of informing the development of targeted therapies for OSCC.

Results: 429 chromatin regulators were screened by a machine learning approach and aberrant expression of SMYD3 was found to be closely associated with OSCC formation and poor prognosis. Data profiling of single-cell and tissue demonstrated that upregulated SMYD3 significantly correlated with aggressive clinicopathological features of OSCC. Alterations in copy number and DNA methylation patterns may contribute to SMYD3 overexpression. Functional experimental results suggested that SMYD3 enhanced cancer cell stemness and proliferation in vitro and tumor growth in vivo. SMYD3 was observed to bind to the High Mobility Group AT-Hook 2 (HMGA2) promoter and elevated tri-methylation of histone H3 lysine 4 at the corresponding site was responsible for transactivating HMGA2. SMYD3 also was positively linked to HMGA2 expression in OSCC samples. Furthermore, treatment with the SMYD3 chemical inhibitor BCI-121 exerted anti-tumor effects.

Conclusions: Histone methyltransferase activity and transcription-potentiating function of SMYD3 were found to be essential for tumorigenesis and the SMYD3-HMGA2 is a potential therapeutic target in OSCC.

背景:表观遗传失调是口腔鳞状细胞癌(OSCC)发生的关键。SET和MYND结构域蛋白3 (SMYD3)是一种组蛋白赖氨酸甲基转移酶,与基因转录调控和肿瘤发生有关。然而,SMYD3在OSCC发生中的作用尚不完全清楚。本研究利用生物信息学方法和验证试验研究了smyd3介导的OSCC肿瘤发生的生物学功能和机制,旨在为OSCC靶向治疗的开发提供信息。结果:通过机器学习方法筛选出429个染色质调节因子,发现SMYD3的异常表达与OSCC的形成和不良预后密切相关。单细胞和组织数据分析表明,SMYD3上调与OSCC侵袭性临床病理特征显著相关。拷贝数和DNA甲基化模式的改变可能导致SMYD3过表达。功能实验结果表明,SMYD3在体外促进癌细胞的干细胞性和增殖,在体内促进肿瘤生长。观察到SMYD3与高迁移率组at - hook 2 (HMGA2)启动子结合,相应位点组蛋白H3赖氨酸4三甲基化升高负责HMGA2的反激活。SMYD3也与OSCC样品中的HMGA2表达呈正相关。此外,用SMYD3化学抑制剂BCI-121治疗具有抗肿瘤作用。结论:组蛋白甲基转移酶活性和SMYD3的转录增强功能在肿瘤发生中至关重要,SMYD3- hmga2是OSCC的潜在治疗靶点。
{"title":"Histone lysine methyltransferase SMYD3 promotes oral squamous cell carcinoma tumorigenesis via H3K4me3-mediated HMGA2 transcription.","authors":"Zongcheng Yang,&nbsp;Fen Liu,&nbsp;Zongkai Li,&nbsp;Nianping Liu,&nbsp;Xinfeng Yao,&nbsp;Yu Zhou,&nbsp;Liyu Zhang,&nbsp;Pan Jiang,&nbsp;Honghong Liu,&nbsp;Lingming Kong,&nbsp;Chuandong Lang,&nbsp;Xin Xu,&nbsp;Jihui Jia,&nbsp;Takahito Nakajima,&nbsp;Wenchao Gu,&nbsp;Lixin Zheng,&nbsp;Zhihong Zhang","doi":"10.1186/s13148-023-01506-9","DOIUrl":"https://doi.org/10.1186/s13148-023-01506-9","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic dysregulation is essential to the tumorigenesis of oral squamous cell carcinoma (OSCC). SET and MYND domain-containing protein 3 (SMYD3), a histone lysine methyltransferase, is implicated in gene transcription regulation and tumor development. However, the roles of SMYD3 in OSCC initiation are not fully understood. The present study investigated the biological functions and mechanisms involved in the SMYD3-mediated tumorigenesis of OSCC utilizing bioinformatic approaches and validation assays with the aim of informing the development of targeted therapies for OSCC.</p><p><strong>Results: </strong>429 chromatin regulators were screened by a machine learning approach and aberrant expression of SMYD3 was found to be closely associated with OSCC formation and poor prognosis. Data profiling of single-cell and tissue demonstrated that upregulated SMYD3 significantly correlated with aggressive clinicopathological features of OSCC. Alterations in copy number and DNA methylation patterns may contribute to SMYD3 overexpression. Functional experimental results suggested that SMYD3 enhanced cancer cell stemness and proliferation in vitro and tumor growth in vivo. SMYD3 was observed to bind to the High Mobility Group AT-Hook 2 (HMGA2) promoter and elevated tri-methylation of histone H3 lysine 4 at the corresponding site was responsible for transactivating HMGA2. SMYD3 also was positively linked to HMGA2 expression in OSCC samples. Furthermore, treatment with the SMYD3 chemical inhibitor BCI-121 exerted anti-tumor effects.</p><p><strong>Conclusions: </strong>Histone methyltransferase activity and transcription-potentiating function of SMYD3 were found to be essential for tumorigenesis and the SMYD3-HMGA2 is a potential therapeutic target in OSCC.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10223939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10045464","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: 1
LEP promoter methylation in the initiation and progression of clonal cytopenia of undetermined significance and myelodysplastic syndrome. LEP启动子甲基化在未确定意义的克隆性细胞减少症和骨髓增生异常综合征的发生和进展中的作用。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-26 DOI: 10.1186/s13148-023-01505-w
Katja Kaastrup, Linn Gillberg, Stine U Mikkelsen, Andreas D Ørskov, Claudia Schöllkopf, Bo K Mortensen, Bo Porse, Jakob W Hansen, Kirsten Grønbæk

Background: Idiopathic non-clonal cytopenia (ICUS) and clonal cytopenia (CCUS) are common in the elderly population. While these entities have similar clinical presentations with peripheral blood cytopenia and less than 10% bone marrow dysplasia, their malignant potential is different and the biological relationship between these disorders and myeloid neoplasms such as myelodysplastic syndrome (MDS) is not fully understood. Aberrant DNA methylation has previously been described to play a vital role in MDS and acute myeloid leukemia (AML) pathogenesis. In addition, obesity confers a poorer prognosis in MDS with inferior overall survival and a higher rate of AML transformation. In this study, we measured DNA methylation of the promoter for the obesity-regulated gene LEP, encoding leptin, in hematopoietic cells from ICUS, CCUS and MDS patients and healthy controls. We investigated whether LEP promoter methylation is an early event in the development of myeloid neoplasms and whether it is associated with clinical outcome.

Results: We found that blood cells of patients with ICUS, CCUS and MDS all have a significantly hypermethylated LEP promoter compared to healthy controls and that LEP hypermethylation is associated with anemia, increased bone marrow blast percentage, and lower plasma leptin levels. MDS patients with a high LEP promoter methylation have a higher risk of progression, shorter progression-free survival, and inferior overall survival. Furthermore, LEP promoter methylation was an independent risk factor for the progression of MDS in a multivariate Cox regression analysis.

Conclusion: In conclusion, hypermethylation of the LEP promoter is an early and frequent event in myeloid neoplasms and is associated with a worse prognosis.

背景:特发性非克隆性细胞减少症(ICUS)和克隆性细胞减少症(CCUS)在老年人群中很常见。虽然这些实体具有相似的临床表现,外周血细胞减少和不到10%的骨髓异常增生,但它们的恶性潜能不同,这些疾病与骨髓增生异常综合征(MDS)等髓系肿瘤之间的生物学关系尚不完全清楚。异常DNA甲基化在MDS和急性髓性白血病(AML)发病机制中起着至关重要的作用。此外,肥胖导致MDS患者预后较差,总生存率较低,AML转化率较高。在这项研究中,我们测量了来自ICUS、CCUS和MDS患者以及健康对照者的造血细胞中肥胖调节基因LEP(编码瘦素)启动子的DNA甲基化。我们研究了LEP启动子甲基化是否是髓系肿瘤发展的早期事件,以及它是否与临床结果相关。结果:我们发现,与健康对照组相比,icu、CCUS和MDS患者的血细胞中LEP启动子都有显著的高甲基化,LEP高甲基化与贫血、骨髓母细胞百分比增加和血浆瘦素水平降低有关。LEP启动子甲基化高的MDS患者有更高的进展风险、更短的无进展生存期和更低的总生存期。此外,在多变量Cox回归分析中,LEP启动子甲基化是MDS进展的独立危险因素。结论:总之,LEP启动子的高甲基化在髓系肿瘤中是一个早期和频繁的事件,并与较差的预后相关。
{"title":"LEP promoter methylation in the initiation and progression of clonal cytopenia of undetermined significance and myelodysplastic syndrome.","authors":"Katja Kaastrup,&nbsp;Linn Gillberg,&nbsp;Stine U Mikkelsen,&nbsp;Andreas D Ørskov,&nbsp;Claudia Schöllkopf,&nbsp;Bo K Mortensen,&nbsp;Bo Porse,&nbsp;Jakob W Hansen,&nbsp;Kirsten Grønbæk","doi":"10.1186/s13148-023-01505-w","DOIUrl":"https://doi.org/10.1186/s13148-023-01505-w","url":null,"abstract":"<p><strong>Background: </strong>Idiopathic non-clonal cytopenia (ICUS) and clonal cytopenia (CCUS) are common in the elderly population. While these entities have similar clinical presentations with peripheral blood cytopenia and less than 10% bone marrow dysplasia, their malignant potential is different and the biological relationship between these disorders and myeloid neoplasms such as myelodysplastic syndrome (MDS) is not fully understood. Aberrant DNA methylation has previously been described to play a vital role in MDS and acute myeloid leukemia (AML) pathogenesis. In addition, obesity confers a poorer prognosis in MDS with inferior overall survival and a higher rate of AML transformation. In this study, we measured DNA methylation of the promoter for the obesity-regulated gene LEP, encoding leptin, in hematopoietic cells from ICUS, CCUS and MDS patients and healthy controls. We investigated whether LEP promoter methylation is an early event in the development of myeloid neoplasms and whether it is associated with clinical outcome.</p><p><strong>Results: </strong>We found that blood cells of patients with ICUS, CCUS and MDS all have a significantly hypermethylated LEP promoter compared to healthy controls and that LEP hypermethylation is associated with anemia, increased bone marrow blast percentage, and lower plasma leptin levels. MDS patients with a high LEP promoter methylation have a higher risk of progression, shorter progression-free survival, and inferior overall survival. Furthermore, LEP promoter methylation was an independent risk factor for the progression of MDS in a multivariate Cox regression analysis.</p><p><strong>Conclusion: </strong>In conclusion, hypermethylation of the LEP promoter is an early and frequent event in myeloid neoplasms and is associated with a worse prognosis.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10224308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9671278","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
Epigenomic profiling of isolated blood cell types reveals highly specific B cell smoking signatures and links to disease risk. 分离的血细胞类型的表观基因组分析揭示了高度特异性的B细胞吸烟特征和与疾病风险的联系。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-25 DOI: 10.1186/s13148-023-01507-8
Xuting Wang, Michelle R Campbell, Hye-Youn Cho, Gary S Pittman, Suzanne N Martos, Douglas A Bell

Background: Tobacco smoking alters the DNA methylation profiles of immune cells which may underpin some of the pathogenesis of smoking-associated diseases. To link smoking-driven epigenetic effects in specific immune cell types with disease risk, we isolated six leukocyte subtypes, CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, CD4+ T cells, CD8+ T cells, and CD56+ natural killer cells, from whole blood of 67 healthy adult smokers and 74 nonsmokers for epigenome-wide association study (EWAS) using Illumina 450k and EPIC methylation arrays.

Results: Numbers of smoking-associated differentially methylated sites (smCpGs) at genome-wide significance (p < 1.2 × 10-7) varied widely across cell types, from 5 smCpGs in CD8+ T cells to 111 smCpGs in CD19+ B cells. We found unique smoking effects in each cell type, some of which were not apparent in whole blood. Methylation-based deconvolution to estimate B cell subtypes revealed that smokers had 7.2% (p = 0.033) less naïve B cells. Adjusting for naïve and memory B cell proportions in EWAS and RNA-seq allowed the identification of genes enriched for B cell activation-related cytokine signaling pathways, Th1/Th2 responses, and hematopoietic cancers. Integrating with large-scale public datasets, 62 smCpGs were among CpGs associated with health-relevant EWASs. Furthermore, 74 smCpGs had reproducible methylation quantitative trait loci single nucleotide polymorphisms (SNPs) that were in complete linkage disequilibrium with genome-wide association study SNPs, associating with lung function, disease risks, and other traits.

Conclusions: We observed blood cell-type-specific smCpGs, a naïve-to-memory shift among B cells, and by integrating genome-wide datasets, we identified their potential links to disease risks and health traits.

背景:吸烟改变了免疫细胞的DNA甲基化特征,这可能是吸烟相关疾病的一些发病机制的基础。为了将吸烟驱动的特定免疫细胞类型的表观遗传学效应与疾病风险联系起来,我们分离了六种白细胞亚型CD14+ 单核细胞,CD15+ 粒细胞,CD19+ B细胞,CD4+ T细胞,CD8+ T细胞和CD56+ 从67名健康成年吸烟者和74名非吸烟者的全血中提取自然杀伤细胞,用于使用Illumina 450k和EPIC甲基化阵列的表观基因组全关联研究(EWAS)。结果:吸烟相关差异甲基化位点(smCpGs)的数量在全基因组显著性(p -7) 细胞类型差异很大,从CD8中的5个smCpG+ T细胞对CD19中111个smCpG的反应+ B细胞。我们在每种细胞类型中都发现了独特的吸烟效应,其中一些在全血中并不明显。基于甲基化的去卷积估计B细胞亚型显示吸烟者有7.2%(p = 0.033)较少幼稚的B细胞。调整EWAS和RNA-seq中幼稚和记忆B细胞的比例,可以鉴定富集B细胞活化相关细胞因子信号通路、Th1/Th2反应和造血癌的基因。与大规模公共数据集集成,62个smCpG属于与健康相关EWAS相关的CpG。此外,74个smCpG具有可重复的甲基化定量性状基因座单核苷酸多态性(SNPs),其与全基因组关联研究SNPs完全连锁不平衡,与肺功能、疾病风险和其他性状相关。结论:我们观察到了血细胞类型特异性smCpG,这是B细胞之间对记忆的幼稚转变,通过整合全基因组数据集,我们确定了它们与疾病风险和健康特征的潜在联系。
{"title":"Epigenomic profiling of isolated blood cell types reveals highly specific B cell smoking signatures and links to disease risk.","authors":"Xuting Wang, Michelle R Campbell, Hye-Youn Cho, Gary S Pittman, Suzanne N Martos, Douglas A Bell","doi":"10.1186/s13148-023-01507-8","DOIUrl":"10.1186/s13148-023-01507-8","url":null,"abstract":"<p><strong>Background: </strong>Tobacco smoking alters the DNA methylation profiles of immune cells which may underpin some of the pathogenesis of smoking-associated diseases. To link smoking-driven epigenetic effects in specific immune cell types with disease risk, we isolated six leukocyte subtypes, CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, CD4+ T cells, CD8+ T cells, and CD56+ natural killer cells, from whole blood of 67 healthy adult smokers and 74 nonsmokers for epigenome-wide association study (EWAS) using Illumina 450k and EPIC methylation arrays.</p><p><strong>Results: </strong>Numbers of smoking-associated differentially methylated sites (smCpGs) at genome-wide significance (p < 1.2 × 10<sup>-7</sup>) varied widely across cell types, from 5 smCpGs in CD8+ T cells to 111 smCpGs in CD19+ B cells. We found unique smoking effects in each cell type, some of which were not apparent in whole blood. Methylation-based deconvolution to estimate B cell subtypes revealed that smokers had 7.2% (p = 0.033) less naïve B cells. Adjusting for naïve and memory B cell proportions in EWAS and RNA-seq allowed the identification of genes enriched for B cell activation-related cytokine signaling pathways, Th1/Th2 responses, and hematopoietic cancers. Integrating with large-scale public datasets, 62 smCpGs were among CpGs associated with health-relevant EWASs. Furthermore, 74 smCpGs had reproducible methylation quantitative trait loci single nucleotide polymorphisms (SNPs) that were in complete linkage disequilibrium with genome-wide association study SNPs, associating with lung function, disease risks, and other traits.</p><p><strong>Conclusions: </strong>We observed blood cell-type-specific smCpGs, a naïve-to-memory shift among B cells, and by integrating genome-wide datasets, we identified their potential links to disease risks and health traits.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10211291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10300130","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
Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas. 联合抑制组蛋白去乙酰化酶和胞苷脱氨酶可提高地西他滨在结直肠癌中的表观遗传效力。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-19 DOI: 10.1186/s13148-023-01500-1
Zijiao Tang, Lu Liu, Jürgen Borlak

Background: Targeting the epigenome of cancerous diseases represents an innovative approach, and the DNA methylation inhibitor decitabine is recommended for the treatment of hematological malignancies. Although epigenetic alterations are also common to solid tumors, the therapeutic efficacy of decitabine in colorectal adenocarcinomas (COAD) is unfavorable. Current research focuses on an identification of combination therapies either with chemotherapeutics or checkpoint inhibitors in modulating the tumor microenvironment. Here we report a series of molecular investigations to evaluate potency of decitabine, the histone deacetylase inhibitor PBA and the cytidine deaminase (CDA) inhibitor tetrahydrouridine (THU) in patient derived functional and p53 null colon cancer cell lines (CCCL). We focused on the inhibition of cell proliferation, the recovery of tumor suppressors and programmed cell death, and established clinical relevance by evaluating drug responsive genes among 270 COAD patients. Furthermore, we evaluated treatment responses based on CpG island density.

Results: Decitabine caused marked repression of the DNMT1 protein. Conversely, PBA treatment of CCCL recovered acetylation of histone 3 lysine residues, and this enabled an open chromatin state. Unlike single decitabine treatment, the combined decitabine/PBA treatment caused > 95% inhibition of cell proliferation, prevented cell cycle progression especially in the S and G2-phase and induced programmed cell death. Decitabine and PBA differed in their ability to facilitate re-expression of genes localized on different chromosomes, and the combined decitabine/PBA treatment was most effective in the re-expression of 40 tumor suppressors and 13 genes typically silenced in cancer-associated genomic regions of COAD patients. Furthermore, this treatment repressed expression of 11 survival (anti-apoptotic) genes and augmented expression of X-chromosome inactivated genes, especially the lncRNA Xist to facilitate p53-mediated apoptosis. Pharmacological inhibition of CDA by THU or its gene knockdown prevented decitabine inactivation. Strikingly, PBA treatment recovered the expression of the decitabine drug-uptake transporter SLC15A1, thus enabling high tumor drug-loads. Finally, for 26 drug responsive genes we demonstrated improved survival in COAD patients.

Conclusion: The combined decitabine/PBA/THU drug treatment improved drug potency considerably, and given their existing regulatory approval, our findings merit prospective clinical trials for the triple combination in COAD patients.

背景:靶向癌性疾病的表观基因组是一种创新的方法,DNA甲基化抑制剂地西他滨被推荐用于血液系统恶性肿瘤的治疗。虽然表观遗传改变在实体瘤中也很常见,但地西他滨在结直肠癌(COAD)中的治疗效果并不理想。目前的研究重点是确定联合化疗药物或检查点抑制剂在调节肿瘤微环境中的作用。在这里,我们报告了一系列分子研究,以评估地西他滨,组蛋白去乙酰化酶抑制剂PBA和胞苷脱氨酶抑制剂四氢吡啶(THU)在患者来源的功能性和p53缺失结肠癌细胞系(CCCL)中的效力。我们关注细胞增殖的抑制、肿瘤抑制因子的恢复和程序性细胞死亡,并通过评估270例COAD患者的药物反应基因来建立临床相关性。此外,我们根据CpG岛密度评估了治疗效果。结果:地西他滨明显抑制DNMT1蛋白。相反,PBA处理CCCL恢复了组蛋白3赖氨酸残基的乙酰化,这使得染色质处于开放状态。与单一地西他滨治疗不同,地西他滨/PBA联合治疗对细胞增殖的抑制作用> 95%,阻止细胞周期进展,特别是在S期和g2期,并诱导程序性细胞死亡。地西他滨和PBA促进不同染色体上基因重新表达的能力不同,地西他滨/PBA联合治疗对COAD患者癌症相关基因组区域中40种肿瘤抑制基因和13种典型沉默基因的重新表达最有效。此外,该处理抑制了11个存活(抗凋亡)基因的表达,增强了x染色体失活基因的表达,特别是lncRNA Xist,促进了p53介导的细胞凋亡。THU或其基因敲低对CDA的药理学抑制可防止地西他滨失活。引人注目的是,PBA治疗恢复了地西他滨药物摄取转运体SLC15A1的表达,从而实现了高肿瘤药物负荷。最后,对于26个药物反应基因,我们证明了COAD患者的生存率提高。结论:地西他滨/PBA/THU联合治疗可显著提高药物效力,鉴于其现有的监管批准,我们的研究结果值得对COAD患者进行三联用药的前瞻性临床试验。
{"title":"Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas.","authors":"Zijiao Tang,&nbsp;Lu Liu,&nbsp;Jürgen Borlak","doi":"10.1186/s13148-023-01500-1","DOIUrl":"https://doi.org/10.1186/s13148-023-01500-1","url":null,"abstract":"<p><strong>Background: </strong>Targeting the epigenome of cancerous diseases represents an innovative approach, and the DNA methylation inhibitor decitabine is recommended for the treatment of hematological malignancies. Although epigenetic alterations are also common to solid tumors, the therapeutic efficacy of decitabine in colorectal adenocarcinomas (COAD) is unfavorable. Current research focuses on an identification of combination therapies either with chemotherapeutics or checkpoint inhibitors in modulating the tumor microenvironment. Here we report a series of molecular investigations to evaluate potency of decitabine, the histone deacetylase inhibitor PBA and the cytidine deaminase (CDA) inhibitor tetrahydrouridine (THU) in patient derived functional and p53 null colon cancer cell lines (CCCL). We focused on the inhibition of cell proliferation, the recovery of tumor suppressors and programmed cell death, and established clinical relevance by evaluating drug responsive genes among 270 COAD patients. Furthermore, we evaluated treatment responses based on CpG island density.</p><p><strong>Results: </strong>Decitabine caused marked repression of the DNMT1 protein. Conversely, PBA treatment of CCCL recovered acetylation of histone 3 lysine residues, and this enabled an open chromatin state. Unlike single decitabine treatment, the combined decitabine/PBA treatment caused > 95% inhibition of cell proliferation, prevented cell cycle progression especially in the S and G2-phase and induced programmed cell death. Decitabine and PBA differed in their ability to facilitate re-expression of genes localized on different chromosomes, and the combined decitabine/PBA treatment was most effective in the re-expression of 40 tumor suppressors and 13 genes typically silenced in cancer-associated genomic regions of COAD patients. Furthermore, this treatment repressed expression of 11 survival (anti-apoptotic) genes and augmented expression of X-chromosome inactivated genes, especially the lncRNA Xist to facilitate p53-mediated apoptosis. Pharmacological inhibition of CDA by THU or its gene knockdown prevented decitabine inactivation. Strikingly, PBA treatment recovered the expression of the decitabine drug-uptake transporter SLC15A1, thus enabling high tumor drug-loads. Finally, for 26 drug responsive genes we demonstrated improved survival in COAD patients.</p><p><strong>Conclusion: </strong>The combined decitabine/PBA/THU drug treatment improved drug potency considerably, and given their existing regulatory approval, our findings merit prospective clinical trials for the triple combination in COAD patients.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10199547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10045442","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: 1
The role of angiotensin I-converting enzyme gene polymorphism and global DNA methylation in the negative associations between urine di-(2-ethylhexyl) phthalate metabolites and serum adiponectin in a young Taiwanese population. 台湾年轻人尿邻苯二甲酸二(2-乙基己基)代谢物与血清脂联素负相关,血管紧张素i转换酶基因多态性与整体DNA甲基化的作用。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-17 DOI: 10.1186/s13148-023-01502-z
Chien-Yu Lin, Hui-Ling Lee, Ching-Way Chen, Chikang Wang, Fung-Chang Sung, Ta-Chen Su

Background: Adiponectin is a key protein produced in adipose tissue, with crucial involvement in multiple metabolic processes. Di-(2-ethylhexyl) phthalate (DEHP), one of the phthalate compounds used as a plasticizer, has been shown to decrease adiponectin levels in vitro and in vivo studies. However, the role of angiotensin I-converting enzyme (ACE) gene polymorphism and epigenetic changes in the relationship between DEHP exposure and adiponectin levels is not well understood.

Methods: This study examined the correlation between urine levels of DEHP metabolite, epigenetic marker 5mdC/dG, ACE gene phenotypes, and adiponectin levels in a sample of 699 individuals aged 12-30 from Taiwan.

Results: Results showed a positive relationship between mono-2-ethylhexyl phthalate (MEHP) and 5mdC/dG, and a negative association between both MEHP and 5mdC/dG with adiponectin. The study found that the inverse relationship between MEHP and adiponectin was stronger when levels of 5mdC/dG were above the median. This was supported by differential unstandardized regression coefficients (- 0.095 vs. - 0.049, P value for interaction = 0.038)). Subgroup analysis also showed a negative correlation between MEHP and adiponectin in individuals with the I/I ACE genotype, but not in those with other genotypes, although the P value for interaction was borderline significant (0.06). The structural equation model analysis indicated that MEHP has a direct inverse effect on adiponectin and an indirect effect via 5mdC/dG.

Conclusions: In this young Taiwanese population, our findings suggest that urine MEHP levels are negatively correlated with serum adiponectin levels, and epigenetic modifications may play a role in this association. Further study is needed to validate these results and determine causality.

背景:脂联素是脂肪组织中产生的一种关键蛋白,在多种代谢过程中起重要作用。邻苯二甲酸二(2-乙基己基)酯(DEHP)是用作增塑剂的邻苯二甲酸酯化合物之一,在体外和体内研究中已被证明可以降低脂联素水平。然而,血管紧张素i转换酶(ACE)基因多态性和表观遗传变化在DEHP暴露与脂联素水平之间的关系中的作用尚不清楚。方法:本研究以台湾地区699名12-30岁人群为样本,检测DEHP代谢物、表观遗传标记物5mdC/dG、ACE基因表型及脂联素水平的相关性。结果:邻苯二甲酸乙二醇酯(MEHP)与5mdC/dG呈正相关,MEHP和5mdC/dG与脂联素呈负相关。研究发现,当5mdC/dG水平高于中位数时,MEHP和脂联素之间的负相关关系更强。差异非标准化回归系数(- 0.095 vs - 0.049,相互作用的P值= 0.038)支持这一点。亚组分析还显示,在I/I ACE基因型个体中,MEHP与脂联素呈负相关,而在其他基因型个体中则无相关,尽管相互作用的P值为临界显著(0.06)。结构方程模型分析表明,MEHP对脂联素具有直接的反向作用,并通过5mdC/dG间接作用。结论:在台湾年轻人群中,我们的研究结果提示尿MEHP水平与血清脂联素水平呈负相关,而表观遗传修饰可能在这种关联中起作用。需要进一步的研究来验证这些结果并确定因果关系。
{"title":"The role of angiotensin I-converting enzyme gene polymorphism and global DNA methylation in the negative associations between urine di-(2-ethylhexyl) phthalate metabolites and serum adiponectin in a young Taiwanese population.","authors":"Chien-Yu Lin,&nbsp;Hui-Ling Lee,&nbsp;Ching-Way Chen,&nbsp;Chikang Wang,&nbsp;Fung-Chang Sung,&nbsp;Ta-Chen Su","doi":"10.1186/s13148-023-01502-z","DOIUrl":"https://doi.org/10.1186/s13148-023-01502-z","url":null,"abstract":"<p><strong>Background: </strong>Adiponectin is a key protein produced in adipose tissue, with crucial involvement in multiple metabolic processes. Di-(2-ethylhexyl) phthalate (DEHP), one of the phthalate compounds used as a plasticizer, has been shown to decrease adiponectin levels in vitro and in vivo studies. However, the role of angiotensin I-converting enzyme (ACE) gene polymorphism and epigenetic changes in the relationship between DEHP exposure and adiponectin levels is not well understood.</p><p><strong>Methods: </strong>This study examined the correlation between urine levels of DEHP metabolite, epigenetic marker 5mdC/dG, ACE gene phenotypes, and adiponectin levels in a sample of 699 individuals aged 12-30 from Taiwan.</p><p><strong>Results: </strong>Results showed a positive relationship between mono-2-ethylhexyl phthalate (MEHP) and 5mdC/dG, and a negative association between both MEHP and 5mdC/dG with adiponectin. The study found that the inverse relationship between MEHP and adiponectin was stronger when levels of 5mdC/dG were above the median. This was supported by differential unstandardized regression coefficients (- 0.095 vs. - 0.049, P value for interaction = 0.038)). Subgroup analysis also showed a negative correlation between MEHP and adiponectin in individuals with the I/I ACE genotype, but not in those with other genotypes, although the P value for interaction was borderline significant (0.06). The structural equation model analysis indicated that MEHP has a direct inverse effect on adiponectin and an indirect effect via 5mdC/dG.</p><p><strong>Conclusions: </strong>In this young Taiwanese population, our findings suggest that urine MEHP levels are negatively correlated with serum adiponectin levels, and epigenetic modifications may play a role in this association. Further study is needed to validate these results and determine causality.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10189977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9671240","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
Retraction Note: Hypermethylation of the 5' CpG island of the p14ARF flanking exon 1β in human colorectal cancer displaying a restricted pattern of p53 overexpression concomitant with increased MDM2 expression. 注:人类结直肠癌中p14ARF侧外显子1β的5' CpG岛的高甲基化显示p53过表达的受限模式伴随着MDM2表达的增加。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-17 DOI: 10.1186/s13148-023-01504-x
Christine Nyiraneza, Christine Sempoux, Roger Detry, Alex Kartheuser, Karin Dahan
{"title":"Retraction Note: Hypermethylation of the 5' CpG island of the p14<sup>ARF</sup> flanking exon 1β in human colorectal cancer displaying a restricted pattern of p53 overexpression concomitant with increased MDM2 expression.","authors":"Christine Nyiraneza,&nbsp;Christine Sempoux,&nbsp;Roger Detry,&nbsp;Alex Kartheuser,&nbsp;Karin Dahan","doi":"10.1186/s13148-023-01504-x","DOIUrl":"https://doi.org/10.1186/s13148-023-01504-x","url":null,"abstract":"","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9860716","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
Traffic-related air pollution and supplemental folic acid intake in relation to DNA methylation in granulosa cells. 交通相关空气污染和补充叶酸摄入量与颗粒细胞 DNA 甲基化的关系。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-13 DOI: 10.1186/s13148-023-01503-y
Audrey J Gaskins, Robert B Hood, Jennifer B Ford, Russ Hauser, Anna K Knight, Alicia K Smith, Todd M Everson

Background: Higher exposure to traffic-related air pollution (TRAP) is related to lower fertility, with specific adverse effects on the ovary. Folic acid may attenuate these effects. Our goal was to explore the relation of TRAP exposure and supplemental folic acid intake with epigenetic aging and CpG-specific DNA methylation (DNAm) in granulosa cells (GC). Our study included 61 women undergoing ovarian stimulation at a fertility center (2005-2015). DNAm levels were profiled in GC using the Infinium MethylationEPIC BeadChip. TRAP was defined using a spatiotemporal model to estimate residence-based nitrogen dioxide (NO2) exposure. Supplemental folic acid intake was measured with a validated food frequency questionnaire. We used linear regression to evaluate whether NO2 or supplemental folic acid was associated with epigenetic age acceleration according to the Pan-tissue, mural GC, and GrimAge clocks or DNAm across the genome adjusting for potential confounders and accounting for multiple testing with a false discovery rate < 0.1.

Results: There were no associations between NO2 or supplemental folic acid intake and epigenetic age acceleration of GC. NO2 and supplemental folic acid were associated with 9 and 11 differentially methylated CpG sites. Among these CpGs, only cg07287107 exhibited a significant interaction (p-value = 0.037). In women with low supplemental folic acid, high NO2 exposure was associated with 1.7% higher DNAm. There was no association between NO2 and DNAm in women with high supplemental folic acid. The genes annotated to the top 250 NO2-associated CpGs were enriched for carbohydrate and protein metabolism, postsynaptic potential and dendrite development, and membrane components and exocytosis. The genes annotated to the top 250 supplemental folic acid-associated CpGs were enriched for estrous cycle, learning, cognition, synaptic organization and transmission, and size and composition of neuronal cell bodies.

Conclusions: We found no associations between NO2, supplemental folic acid, and DNAm age acceleration of GC. However, there were 20 differentially methylated CpGs and multiple enriched GO terms associated with both exposures suggesting that differences in GC DNAm could be a plausible mechanism underlying the effects of TRAP and supplemental folic acid on ovarian function.

背景:较高的交通相关空气污染(TRAP)暴露与较低的生育能力有关,对卵巢有特定的不利影响。叶酸可减轻这些影响。我们的目的是探讨TRAP暴露和叶酸补充摄入量与粒细胞(GC)表观遗传老化和CpG特异性DNA甲基化(DNAm)的关系。我们的研究纳入了 61 名在生殖中心接受卵巢刺激的女性(2005-2015 年)。使用 Infinium MethylationEPIC BeadChip 分析了颗粒细胞中的 DNAm 水平。使用时空模型估算了基于居住地的二氧化氮(NO2)暴露,从而确定了TRAP。补充叶酸的摄入量通过有效的食物频率问卷进行测量。我们使用线性回归法评估了二氧化氮或补充叶酸是否与泛组织、壁面 GC 和 GrimAge 时钟或整个基因组的 DNAm 的表观遗传年龄加速有关,并对潜在的混杂因素进行了调整,同时考虑了假发现率的多重测试 结果:二氧化氮或补充叶酸的摄入与 GC 的表观遗传年龄加速之间没有关联。二氧化氮和补充叶酸分别与 9 个和 11 个不同的甲基化 CpG 位点有关。在这些 CpGs 中,只有 cg07287107 显示出显著的交互作用(p 值 = 0.037)。在补充叶酸较少的妇女中,高浓度的二氧化氮暴露与 DNAm 高出 1.7% 有关。在补充叶酸较多的妇女中,二氧化氮与 DNAm 之间没有关联。注释到与 NO2 相关的前 250 个 CpGs 的基因富含碳水化合物和蛋白质代谢、突触后电位和树突发育以及膜成分和外吞。与补充叶酸相关的前250个CpGs注释的基因富集于发情周期、学习、认知、突触组织和传递以及神经元细胞体的大小和组成:我们没有发现 NO2、补充叶酸和 DNAm 年龄加速 GC 之间的关联。然而,有20个不同的甲基化CpGs和多个富集的GO术语与这两种暴露相关,这表明GC DNAm的差异可能是TRAP和补充叶酸对卵巢功能影响的一个合理机制。
{"title":"Traffic-related air pollution and supplemental folic acid intake in relation to DNA methylation in granulosa cells.","authors":"Audrey J Gaskins, Robert B Hood, Jennifer B Ford, Russ Hauser, Anna K Knight, Alicia K Smith, Todd M Everson","doi":"10.1186/s13148-023-01503-y","DOIUrl":"10.1186/s13148-023-01503-y","url":null,"abstract":"<p><strong>Background: </strong>Higher exposure to traffic-related air pollution (TRAP) is related to lower fertility, with specific adverse effects on the ovary. Folic acid may attenuate these effects. Our goal was to explore the relation of TRAP exposure and supplemental folic acid intake with epigenetic aging and CpG-specific DNA methylation (DNAm) in granulosa cells (GC). Our study included 61 women undergoing ovarian stimulation at a fertility center (2005-2015). DNAm levels were profiled in GC using the Infinium MethylationEPIC BeadChip. TRAP was defined using a spatiotemporal model to estimate residence-based nitrogen dioxide (NO<sub>2</sub>) exposure. Supplemental folic acid intake was measured with a validated food frequency questionnaire. We used linear regression to evaluate whether NO<sub>2</sub> or supplemental folic acid was associated with epigenetic age acceleration according to the Pan-tissue, mural GC, and GrimAge clocks or DNAm across the genome adjusting for potential confounders and accounting for multiple testing with a false discovery rate < 0.1.</p><p><strong>Results: </strong>There were no associations between NO<sub>2</sub> or supplemental folic acid intake and epigenetic age acceleration of GC. NO<sub>2</sub> and supplemental folic acid were associated with 9 and 11 differentially methylated CpG sites. Among these CpGs, only cg07287107 exhibited a significant interaction (p-value = 0.037). In women with low supplemental folic acid, high NO<sub>2</sub> exposure was associated with 1.7% higher DNAm. There was no association between NO<sub>2</sub> and DNAm in women with high supplemental folic acid. The genes annotated to the top 250 NO<sub>2</sub>-associated CpGs were enriched for carbohydrate and protein metabolism, postsynaptic potential and dendrite development, and membrane components and exocytosis. The genes annotated to the top 250 supplemental folic acid-associated CpGs were enriched for estrous cycle, learning, cognition, synaptic organization and transmission, and size and composition of neuronal cell bodies.</p><p><strong>Conclusions: </strong>We found no associations between NO<sub>2</sub>, supplemental folic acid, and DNAm age acceleration of GC. However, there were 20 differentially methylated CpGs and multiple enriched GO terms associated with both exposures suggesting that differences in GC DNAm could be a plausible mechanism underlying the effects of TRAP and supplemental folic acid on ovarian function.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10183139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9474840","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
Short-chain fatty acid-butyric acid ameliorates granulosa cells inflammation through regulating METTL3-mediated N6-methyladenosine modification of FOSL2 in polycystic ovarian syndrome. 短链脂肪酸-丁酸通过调节mettl3介导的FOSL2的n6 -甲基腺苷修饰改善多囊卵巢综合征颗粒细胞炎症。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-13 DOI: 10.1186/s13148-023-01487-9
Kailu Liu, Xi He, Jingyu Huang, Simin Yu, Meiting Cui, Mengya Gao, Li Liu, Yu Qian, Ying Xie, Miao Hui, Yanli Hong, Xiaowei Nie

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by chronic low-grade inflammation. Previous studies have demonstrated that the gut microbiome can affect the host tissue cells' mRNA N6-methyladenosine (m6A) modifications. This study aimed to understand the role of intestinal flora in ovarian cells inflammation by regulating mRNA m6A modification particularly the inflammatory state in PCOS. The gut microbiome composition of PCOS and Control groups was analyzed by 16S rRNA sequencing, and the short chain fatty acids were detected in patients' serum by mass spectrometry methods. The level of butyric acid was found to be decreased in the serum of the obese PCOS group (FAT) compared to other groups, and this was correlated with increased Streptococcaceae and decreased Rikenellaceae based on the Spearman's rank test. Additionally, we identified FOSL2 as a potential METTL3 target using RNA-seq and MeRIP-seq methodologies. Cellular experiments demonstrated that the addition of butyric acid led to a decrease in FOSL2 m6A methylation levels and mRNA expression by suppressing the expression of METTL3, an m6A methyltransferase. Additionally, NLRP3 protein expression and the expression of inflammatory cytokines (IL-6 and TNF-α) were downregulated in KGN cells. Butyric acid supplementation in obese PCOS mice improved ovarian function and decreased the expression of local inflammatory factors in the ovary. Taken together, the correlation between the gut microbiome and PCOS may unveil crucial mechanisms for the role of specific gut microbiota in the pathogenesis of PCOS. Furthermore, butyric acid may present new prospects for future PCOS treatments.

多囊卵巢综合征(PCOS)是一种以慢性低度炎症为特征的内分泌代谢紊乱。先前的研究表明,肠道微生物组可以影响宿主组织细胞mRNA n6 -甲基腺苷(m6A)的修饰。本研究旨在了解肠道菌群在卵巢细胞炎症中的作用,通过调节mRNA m6A修饰,特别是PCOS的炎症状态。采用16S rRNA测序分析PCOS组和对照组的肠道微生物组组成,采用质谱法检测患者血清中的短链脂肪酸。与其他组相比,肥胖PCOS组(FAT)血清中丁酸水平降低,根据Spearman秩检验,这与链球菌科增加和里氏杆菌科减少相关。此外,我们使用RNA-seq和MeRIP-seq方法确定FOSL2是潜在的METTL3靶点。细胞实验表明,丁酸的加入通过抑制m6A甲基转移酶METTL3的表达,导致FOSL2 m6A甲基化水平和mRNA表达的降低。KGN细胞NLRP3蛋白表达下调,炎症因子IL-6、TNF-α表达下调。肥胖PCOS小鼠补充丁酸可改善卵巢功能,降低卵巢局部炎症因子的表达。综上所述,肠道微生物群与多囊卵巢综合征之间的相关性可能揭示特定肠道微生物群在多囊卵巢综合征发病机制中的重要作用。此外,丁酸可能是未来多囊卵巢综合征治疗的新前景。
{"title":"Short-chain fatty acid-butyric acid ameliorates granulosa cells inflammation through regulating METTL3-mediated N6-methyladenosine modification of FOSL2 in polycystic ovarian syndrome.","authors":"Kailu Liu,&nbsp;Xi He,&nbsp;Jingyu Huang,&nbsp;Simin Yu,&nbsp;Meiting Cui,&nbsp;Mengya Gao,&nbsp;Li Liu,&nbsp;Yu Qian,&nbsp;Ying Xie,&nbsp;Miao Hui,&nbsp;Yanli Hong,&nbsp;Xiaowei Nie","doi":"10.1186/s13148-023-01487-9","DOIUrl":"https://doi.org/10.1186/s13148-023-01487-9","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by chronic low-grade inflammation. Previous studies have demonstrated that the gut microbiome can affect the host tissue cells' mRNA N6-methyladenosine (m6A) modifications. This study aimed to understand the role of intestinal flora in ovarian cells inflammation by regulating mRNA m6A modification particularly the inflammatory state in PCOS. The gut microbiome composition of PCOS and Control groups was analyzed by 16S rRNA sequencing, and the short chain fatty acids were detected in patients' serum by mass spectrometry methods. The level of butyric acid was found to be decreased in the serum of the obese PCOS group (FAT) compared to other groups, and this was correlated with increased Streptococcaceae and decreased Rikenellaceae based on the Spearman's rank test. Additionally, we identified FOSL2 as a potential METTL3 target using RNA-seq and MeRIP-seq methodologies. Cellular experiments demonstrated that the addition of butyric acid led to a decrease in FOSL2 m6A methylation levels and mRNA expression by suppressing the expression of METTL3, an m6A methyltransferase. Additionally, NLRP3 protein expression and the expression of inflammatory cytokines (IL-6 and TNF-α) were downregulated in KGN cells. Butyric acid supplementation in obese PCOS mice improved ovarian function and decreased the expression of local inflammatory factors in the ovary. Taken together, the correlation between the gut microbiome and PCOS may unveil crucial mechanisms for the role of specific gut microbiota in the pathogenesis of PCOS. Furthermore, butyric acid may present new prospects for future PCOS treatments.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10183145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9474843","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
Epigenetic effects of herbal medicine. 草药的表观遗传效应。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-13 DOI: 10.1186/s13148-023-01481-1
Yu-Yao Wu, Yan-Ming Xu, Andy T Y Lau

Epigenetic memory is essential for life that governs the predefined functional features of cells. Recent evidence has indicated that the epigenetic modification provides a potential link to gene expression changes that may be involved in the development of various chronic diseases, and targeting the epigenome becomes a plausible method for treating diseases. Traditional herbal medicine has gradually entered the vision of researchers due to its low toxicity and its effectiveness in treating diseases. As a matter of fact, researchers found that the possessed epigenetic modification capacity of herbal medicine had the ability to combat the progression of the disease, such as various types of cancer, diabetes, inflammation, amnesia, liver fibrosis, asthma, and hypertension-induced renal injury. Studies on the epigenetic effects of herbal medicine will provide valuable insights into the molecular mechanisms of human diseases, which may lead to new therapeutic approaches and diagnoses. Thus, this review summarized the impact of herbal medicine and its bioactive components on disease epigenome as examples of how utilization of epigenetic plasticity could be useful as the basis for the future development of targeted therapies in chronic diseases.

表观遗传记忆是控制细胞预定义功能特征的生命所必需的。最近的证据表明,表观遗传修饰提供了可能参与各种慢性疾病发展的基因表达变化的潜在联系,并且靶向表观基因组成为治疗疾病的可行方法。传统草药以其低毒性和治疗疾病的功效逐渐进入研究者的视野。事实上,研究人员发现,草药所具有的表观遗传修饰能力具有对抗疾病进展的能力,如各种类型的癌症、糖尿病、炎症、健忆症、肝纤维化、哮喘和高血压引起的肾损伤。对草药表观遗传效应的研究将为人类疾病的分子机制提供有价值的见解,这可能会导致新的治疗方法和诊断。因此,本文综述了草药及其生物活性成分对疾病表观基因组的影响,并举例说明如何利用表观遗传可塑性作为未来发展慢性疾病靶向治疗的基础。
{"title":"Epigenetic effects of herbal medicine.","authors":"Yu-Yao Wu,&nbsp;Yan-Ming Xu,&nbsp;Andy T Y Lau","doi":"10.1186/s13148-023-01481-1","DOIUrl":"https://doi.org/10.1186/s13148-023-01481-1","url":null,"abstract":"<p><p>Epigenetic memory is essential for life that governs the predefined functional features of cells. Recent evidence has indicated that the epigenetic modification provides a potential link to gene expression changes that may be involved in the development of various chronic diseases, and targeting the epigenome becomes a plausible method for treating diseases. Traditional herbal medicine has gradually entered the vision of researchers due to its low toxicity and its effectiveness in treating diseases. As a matter of fact, researchers found that the possessed epigenetic modification capacity of herbal medicine had the ability to combat the progression of the disease, such as various types of cancer, diabetes, inflammation, amnesia, liver fibrosis, asthma, and hypertension-induced renal injury. Studies on the epigenetic effects of herbal medicine will provide valuable insights into the molecular mechanisms of human diseases, which may lead to new therapeutic approaches and diagnoses. Thus, this review summarized the impact of herbal medicine and its bioactive components on disease epigenome as examples of how utilization of epigenetic plasticity could be useful as the basis for the future development of targeted therapies in chronic diseases.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10183144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9474842","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: 1
Capturing sex-specific and hypofertility-linked effects of assisted reproductive technologies on the cord blood DNA methylome. 捕获辅助生殖技术对脐带血DNA甲基化的性别特异性和低生育能力相关影响。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-11 DOI: 10.1186/s13148-023-01497-7
Sophia Rahimi, Xiaojian Shao, Donovan Chan, Josée Martel, Anick Bérard, William D Fraser, Marie-Michelle Simon, Tony Kwan, Guillaume Bourque, Jacquetta Trasler

Background: Children conceived through assisted reproduction are at an increased risk for growth and genomic imprinting disorders, often linked to DNA methylation defects. It has been suggested that assisted reproductive technology (ART) and underlying parental infertility can induce epigenetic instability, specifically interfering with DNA methylation reprogramming events during germ cell and preimplantation development. To date, human studies exploring the association between ART and DNA methylation defects have reported inconsistent or inconclusive results, likely due to population heterogeneity and the use of technologies with limited coverage of the epigenome. In our study, we explored the epigenetic risk of ART by comprehensively profiling the DNA methylome of 73 human cord blood samples of singleton pregnancies (n = 36 control group, n = 37 ART/hypofertile group) from a human prospective longitudinal birth cohort, the 3D (Design, Develop, Discover) Study, using a high-resolution sequencing-based custom capture panel that examines over 2.4 million autosomal CpGs in the genome.

Results: We identified evidence of sex-specific effects of ART/hypofertility on cord blood DNA methylation patterns. Our genome-wide analyses identified ~ 46% more CpGs affected by ART/hypofertility in female than in male infant cord blood. We performed a detailed analysis of three imprinted genes which have been associated with altered DNA methylation following ART (KCNQ1OT1, H19/IGF2 and GNAS) and found that female infant cord blood was associated with DNA hypomethylation. When compared to less invasive procedures such as intrauterine insemination, more invasive ARTs (in vitro fertilization, intracytoplasmic sperm injection, embryo culture) resulted in more marked and distinct effects on the cord blood DNA methylome. In the in vitro group, we found a close to fourfold higher proportion of significantly enriched Gene Ontology terms involved in development than in the in vivo group.

Conclusions: Our study highlights the ability of a sensitive, targeted, sequencing-based approach to uncover DNA methylation perturbations in cord blood associated with hypofertility and ART and influenced by offspring sex and ART technique invasiveness.

背景:通过辅助生殖受孕的儿童生长和基因组印记障碍的风险增加,通常与DNA甲基化缺陷有关。已有研究表明,辅助生殖技术(ART)和潜在的亲代不育可诱导表观遗传不稳定,特别是干扰生殖细胞和着床前发育过程中的DNA甲基化重编程事件。迄今为止,探索ART与DNA甲基化缺陷之间关系的人类研究报告了不一致或不确定的结果,可能是由于群体异质性和使用的技术对表观基因组的覆盖范围有限。在我们的研究中,我们通过全面分析来自人类前瞻性纵向出生队列3D(设计、开发、发现)研究的73例单胎妊娠人类脐带血样本(n = 36对照组,n = 37 ART/低生育能力组)的DNA甲基化组,探索了ART的表观遗传风险,使用基于高分辨率测序的自定义捕获面板,检查了基因组中超过240万个常染色体CpGs。结果:我们发现了ART/低生育能力对脐带血DNA甲基化模式的性别特异性影响的证据。我们的全基因组分析发现,受抗逆转录病毒治疗/生育能力低下影响的CpGs在女性中比在男性婴儿脐带血中多46%。我们对三个与ART后DNA甲基化改变相关的印迹基因(kcnq10t1、H19/IGF2和GNAS)进行了详细分析,发现女婴脐带血与DNA低甲基化有关。与侵入性较低的程序(如宫内人工授精)相比,侵入性较强的人工授精(体外受精、胞浆内精子注射、胚胎培养)对脐带血DNA甲基化组的影响更为显著和明显。在体外组中,我们发现与发育相关的显著富集的基因本体术语的比例比体内组高出近四倍。结论:我们的研究强调了一种敏感的、有针对性的、基于测序的方法的能力,该方法可以揭示与生育能力低下和抗逆转录病毒治疗相关的脐带血DNA甲基化扰动,并受后代性别和抗逆转录病毒治疗技术侵入性的影响。
{"title":"Capturing sex-specific and hypofertility-linked effects of assisted reproductive technologies on the cord blood DNA methylome.","authors":"Sophia Rahimi,&nbsp;Xiaojian Shao,&nbsp;Donovan Chan,&nbsp;Josée Martel,&nbsp;Anick Bérard,&nbsp;William D Fraser,&nbsp;Marie-Michelle Simon,&nbsp;Tony Kwan,&nbsp;Guillaume Bourque,&nbsp;Jacquetta Trasler","doi":"10.1186/s13148-023-01497-7","DOIUrl":"https://doi.org/10.1186/s13148-023-01497-7","url":null,"abstract":"<p><strong>Background: </strong>Children conceived through assisted reproduction are at an increased risk for growth and genomic imprinting disorders, often linked to DNA methylation defects. It has been suggested that assisted reproductive technology (ART) and underlying parental infertility can induce epigenetic instability, specifically interfering with DNA methylation reprogramming events during germ cell and preimplantation development. To date, human studies exploring the association between ART and DNA methylation defects have reported inconsistent or inconclusive results, likely due to population heterogeneity and the use of technologies with limited coverage of the epigenome. In our study, we explored the epigenetic risk of ART by comprehensively profiling the DNA methylome of 73 human cord blood samples of singleton pregnancies (n = 36 control group, n = 37 ART/hypofertile group) from a human prospective longitudinal birth cohort, the 3D (Design, Develop, Discover) Study, using a high-resolution sequencing-based custom capture panel that examines over 2.4 million autosomal CpGs in the genome.</p><p><strong>Results: </strong>We identified evidence of sex-specific effects of ART/hypofertility on cord blood DNA methylation patterns. Our genome-wide analyses identified ~ 46% more CpGs affected by ART/hypofertility in female than in male infant cord blood. We performed a detailed analysis of three imprinted genes which have been associated with altered DNA methylation following ART (KCNQ1OT1, H19/IGF2 and GNAS) and found that female infant cord blood was associated with DNA hypomethylation. When compared to less invasive procedures such as intrauterine insemination, more invasive ARTs (in vitro fertilization, intracytoplasmic sperm injection, embryo culture) resulted in more marked and distinct effects on the cord blood DNA methylome. In the in vitro group, we found a close to fourfold higher proportion of significantly enriched Gene Ontology terms involved in development than in the in vivo group.</p><p><strong>Conclusions: </strong>Our study highlights the ability of a sensitive, targeted, sequencing-based approach to uncover DNA methylation perturbations in cord blood associated with hypofertility and ART and influenced by offspring sex and ART technique invasiveness.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10176895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9845485","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: 1
期刊
Clinical Epigenetics
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1