Institut National de la Santé Et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR)_1090, Aix Marseille Université, TAGC Theories and Approaches of Genomic Complexity, Institut MarMaRa, Marseille, France.
Laboratory of Immunology, Heart Institute Instituto do Coração (InCor), University of São Paulo, School of Medicine, São Paulo, Brazil.
Front Immunol. 2022 Aug 22;13:958200. doi: 10.3389/fimmu.2022.958200. eCollection 2022.
Chagas disease, caused by the protozoan , is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease.
恰加斯病由原生动物引起，是拉丁美洲流行的寄生虫病，影响 700 万人。虽然大多数患者无症状，但 30%的患者会出现并发症，包括经常致命的慢性恰加斯心肌病（CCC）。尽管先前的研究已经证明了一些与 CCC 相关的遗传失调，但它们失调的原因仍描述不足。基于批量 RNA-seq 和全基因组 DNA 甲基化数据，我们研究了 CCC 中中度和重度阶段存在的遗传和表观遗传失调。对心脏组织基因表达谱的分析使我们能够识别出 1407 个特定于 CCC 患者的差异表达转录本（DEGs）。对同一组织进行的组织 DNA 甲基化分析允许确定 92 个位于 DEGs 启动子中的调控性差异甲基化区域（DMR）。对 DMR 中转录因子结合位点（TFBS）的深入研究证实了 TFBS 的 DNA 甲基化对 CCC 心肌中基因表达的重要性。TBX21、RUNX3 和 EBF1 是转录因子，其结合基序似乎受到最大数量基因的 DNA 甲基化影响。通过对心脏组织进行转录组和甲基组分析以及对血液进行甲基组分析，确定了 4 个受严重 CCC 影响的生物学过程，包括免疫反应、离子转运、心肌过程和神经系统。对中度 CCC 样本血液甲基化的进一步研究提出了离子转运和神经系统在疾病发展中的重要性。
