{"title":"急性心肌梗死患者 cfDNA 不同的甲基组图谱显示,调控心肌收缩的 cAMP 信号通路基因发生了显著变化。","authors":"Manoswini Dash, Bhawna Mahajan, Shobhita Shah, Ghulam Mehdi Dar, Parameswar Sahu, Abhay Kumar Sharma, Nimisha, Sundeep Singh Saluja","doi":"10.1186/s13148-024-01755-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The role of epigenetics in cardiovascular diseases has paved the way for innovative therapeutic approaches. Investigating epigenetic changes using cell-free DNA (cfDNA) holds substantial promise beyond mere diagnostics, especially for heart-related conditions like acute myocardial infarction (AMI), where obtaining tissue samples is a challenge. This study explores the methylation patterns of cfDNA in AMI patients and compares them with genomic DNA (gDNA) from the same individuals, aiming to evaluate the effectiveness of cfDNA as a valuable resource for studying heart-related diseases.</p><p><strong>Methodology: </strong>We generated global methylome profiles of cfDNA and gDNA from 25 AMI patients using EM-Seq. Tissue deconvolution analysis was performed to estimate tissue specificity based on the methylation patterns. Differentially methylated loci were identified and explored to understand AMI pathophysiology.</p><p><strong>Results: </strong>Comparative analysis of cfDNA and gDNA methylation patterns in AMI patients reveals cfDNA holds more significance than gDNA. Principal component analysis revealed distinct clusters for cfDNA and gDNA, indicating distinct methylome profiles. cfDNA originated from multiple sources, predominantly from neutrophils (~ 75%) and about 10% from the left atrium, highlighting cardiac-specific changes. In contrast, immune cells are the major source of gDNA, indicative of inflammatory responses. Gene set enrichment analysis (GSEA) associates cfDNA methylation patterns with pathways related to cardiac muscle contraction, inflammation, hypoxia, and lipid metabolism. The affected genes include G protein-coupled receptors (GHSR, FFAR2, HTR1A, and VIPR2) that are part of the cAMP signaling pathway.</p><p><strong>Conclusion: </strong>Epigenetic changes in cfDNA are more specific to cardiac tissue compared to those in gDNA, providing better insights into the molecular mechanisms involved in AMI. Genes that are differentially methylated in cfDNA and regulate core pathways, such as cAMP signaling, could be targeted for clinical applications, including the development of effective biomarkers and therapeutic targets.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"16 1","pages":"144"},"PeriodicalIF":4.8000,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484321/pdf/","citationCount":"0","resultStr":"{\"title\":\"Distinct methylome profile of cfDNA in AMI patients reveals significant alteration in cAMP signaling pathway genes regulating cardiac muscle contraction.\",\"authors\":\"Manoswini Dash, Bhawna Mahajan, Shobhita Shah, Ghulam Mehdi Dar, Parameswar Sahu, Abhay Kumar Sharma, Nimisha, Sundeep Singh Saluja\",\"doi\":\"10.1186/s13148-024-01755-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The role of epigenetics in cardiovascular diseases has paved the way for innovative therapeutic approaches. Investigating epigenetic changes using cell-free DNA (cfDNA) holds substantial promise beyond mere diagnostics, especially for heart-related conditions like acute myocardial infarction (AMI), where obtaining tissue samples is a challenge. This study explores the methylation patterns of cfDNA in AMI patients and compares them with genomic DNA (gDNA) from the same individuals, aiming to evaluate the effectiveness of cfDNA as a valuable resource for studying heart-related diseases.</p><p><strong>Methodology: </strong>We generated global methylome profiles of cfDNA and gDNA from 25 AMI patients using EM-Seq. Tissue deconvolution analysis was performed to estimate tissue specificity based on the methylation patterns. Differentially methylated loci were identified and explored to understand AMI pathophysiology.</p><p><strong>Results: </strong>Comparative analysis of cfDNA and gDNA methylation patterns in AMI patients reveals cfDNA holds more significance than gDNA. Principal component analysis revealed distinct clusters for cfDNA and gDNA, indicating distinct methylome profiles. cfDNA originated from multiple sources, predominantly from neutrophils (~ 75%) and about 10% from the left atrium, highlighting cardiac-specific changes. In contrast, immune cells are the major source of gDNA, indicative of inflammatory responses. Gene set enrichment analysis (GSEA) associates cfDNA methylation patterns with pathways related to cardiac muscle contraction, inflammation, hypoxia, and lipid metabolism. The affected genes include G protein-coupled receptors (GHSR, FFAR2, HTR1A, and VIPR2) that are part of the cAMP signaling pathway.</p><p><strong>Conclusion: </strong>Epigenetic changes in cfDNA are more specific to cardiac tissue compared to those in gDNA, providing better insights into the molecular mechanisms involved in AMI. Genes that are differentially methylated in cfDNA and regulate core pathways, such as cAMP signaling, could be targeted for clinical applications, including the development of effective biomarkers and therapeutic targets.</p>\",\"PeriodicalId\":10366,\"journal\":{\"name\":\"Clinical Epigenetics\",\"volume\":\"16 1\",\"pages\":\"144\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2024-10-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484321/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Epigenetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13148-024-01755-2\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Epigenetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13148-024-01755-2","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
摘要
背景:表观遗传学在心血管疾病中的作用为创新治疗方法铺平了道路。利用无细胞 DNA(cfDNA)研究表观遗传学的变化不仅具有诊断意义,而且前景广阔,特别是对于急性心肌梗塞(AMI)等心脏相关疾病,因为在这些疾病中获取组织样本是一项挑战。本研究探讨了急性心肌梗塞患者体内 cfDNA 的甲基化模式,并将其与来自同一个体的基因组 DNA(gDNA)进行了比较,旨在评估 cfDNA 作为研究心脏相关疾病的宝贵资源的有效性:我们利用EM-Seq技术生成了25名AMI患者的cfDNA和gDNA的全局甲基组图谱。根据甲基化模式进行组织解卷积分析,以估计组织特异性。确定并探索了不同的甲基化位点,以了解 AMI 病理生理学:结果:对 AMI 患者中 cfDNA 和 gDNA 甲基化模式的比较分析表明,cfDNA 比 gDNA 更重要。cfDNA来自多个来源,主要来自中性粒细胞(约75%),约10%来自左心房,突显了心脏特异性变化。相比之下,免疫细胞是 gDNA 的主要来源,表明了炎症反应。基因组富集分析(GSEA)将 cfDNA 甲基化模式与心肌收缩、炎症、缺氧和脂质代谢相关的通路联系起来。受影响的基因包括属于 cAMP 信号通路的 G 蛋白偶联受体(GHSR、FFAR2、HTR1A 和 VIPR2):cfDNA中的表观遗传变化与gDNA中的表观遗传变化相比,对心脏组织更具特异性,能更好地揭示AMI的分子机制。cfDNA中不同程度甲基化并调控cAMP信号转导等核心通路的基因可作为临床应用的目标,包括开发有效的生物标记物和治疗靶点。
Distinct methylome profile of cfDNA in AMI patients reveals significant alteration in cAMP signaling pathway genes regulating cardiac muscle contraction.
Background: The role of epigenetics in cardiovascular diseases has paved the way for innovative therapeutic approaches. Investigating epigenetic changes using cell-free DNA (cfDNA) holds substantial promise beyond mere diagnostics, especially for heart-related conditions like acute myocardial infarction (AMI), where obtaining tissue samples is a challenge. This study explores the methylation patterns of cfDNA in AMI patients and compares them with genomic DNA (gDNA) from the same individuals, aiming to evaluate the effectiveness of cfDNA as a valuable resource for studying heart-related diseases.
Methodology: We generated global methylome profiles of cfDNA and gDNA from 25 AMI patients using EM-Seq. Tissue deconvolution analysis was performed to estimate tissue specificity based on the methylation patterns. Differentially methylated loci were identified and explored to understand AMI pathophysiology.
Results: Comparative analysis of cfDNA and gDNA methylation patterns in AMI patients reveals cfDNA holds more significance than gDNA. Principal component analysis revealed distinct clusters for cfDNA and gDNA, indicating distinct methylome profiles. cfDNA originated from multiple sources, predominantly from neutrophils (~ 75%) and about 10% from the left atrium, highlighting cardiac-specific changes. In contrast, immune cells are the major source of gDNA, indicative of inflammatory responses. Gene set enrichment analysis (GSEA) associates cfDNA methylation patterns with pathways related to cardiac muscle contraction, inflammation, hypoxia, and lipid metabolism. The affected genes include G protein-coupled receptors (GHSR, FFAR2, HTR1A, and VIPR2) that are part of the cAMP signaling pathway.
Conclusion: Epigenetic changes in cfDNA are more specific to cardiac tissue compared to those in gDNA, providing better insights into the molecular mechanisms involved in AMI. Genes that are differentially methylated in cfDNA and regulate core pathways, such as cAMP signaling, could be targeted for clinical applications, including the development of effective biomarkers and therapeutic targets.
期刊介绍:
Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.