DNA methylation, 3D genome organization and gene expression during Trichomonas vaginalis: host interaction

阴道毛滴虫期间的 DNA 甲基化、3D 基因组组织和基因表达：宿主相互作用

• 批准号: 10449813
• 负责人: Pablo Hernan Strobl Mazzulla
• 金额: $ 13.37万
• 依托单位: INSTITUTE/RESEARCH/BIOTECHNOLOGY FDN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-07 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449813
• 关键词: 3-Dimensional; ATAC-seq; Adenine; Adherence; Affect; Antibodies; Architecture; Bioinformatics; Biological Assay; Birth; Cell Communication; Cell Nucleus; Cells; Cervicitis; Chromatin; Chromatin Loop; Chromatin Structure; Code; DNA; DNA Methylation; DNA Transposable Elements; Data; Epigenetic Process; Epitopes; Etiology; Eukaryota; Foundations; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Goals; HIV; HIV Infections; Health; Histone Acetylation; Human; Infection; Infertility; Inflammatory; Intercistronic Region; Lead; Malignant neoplasm of cervix uteri; Malignant neoplasm of prostate; Mastigophora; Methylation; Modeling; Molecular; Molecular Biology Techniques; Molecular Conformation; Nuclear; Outcome; Outcome Study; Parasites; Parasitic infection; Parasitology; Pathogenesis; Pelvic Inflammatory Disease; Peptides; Play; Predisposition; Pregnancy; Premature Birth; Process; Proteins; Public Health; Regulation; Regulator Genes; Regulatory Element; Research; Resistance; Risk; Role; Sexual Transmission; Sexually Transmitted Diseases; Structure; Testing; Transcriptional Regulation; Trichomonas; Trichomonas Infections; Trichomonas vaginalis; Urethritis; Vaginitis; Woman; Work; base; chromosome conformation capture; chronic infection; cytotoxicity; epigenetic regulation; epigenome editing; experimental study; extracellular; genome-wide; insight; new therapeutic target; next generation sequencing; novel; preference; recruit; tool; transcriptome; transcriptome sequencing; urogenital tract

DNA methylation, 3D genome organization and gene expression during Trichomonas vaginalis: host interaction ABSTRACT Trichomonas vaginalis is a common sexually transmitted parasite that colonizes the human urogenital tract causing infections that range from asymptomatic to highly inflammatory. Chronic infections can lead to severe complications such as infertility, premature birth during pregnancy, increases the risk of acquiring HIV, cervical cancer and aggressive prostate cancer. Hence, understanding how the process of infection in Trichomonas parasite is regulated remains an important goal in parasitology research and human health. Host: parasite interaction is regulated by changes in gene expression, but it is still largely unknown how these changes in transcriptional profiles are controlled as very few transcriptional regulatory elements have been described. Our recent works highlighted the importance of epigenetics in the regulation of transcription and possible role in parasite pathogenesis. Specifically, we analyzed the abundance of DNA methylation demonstrating that N6-methyladenine (6mA), and not 5‐methylcytosine (5mC), is the main DNA methylation mark in T. vaginalis. Genome-wide distribution of 6mA reveals that this mark is enriched at intergenic regions, with a preference for certain superfamilies of DNA transposable elements. Interestingly, bioinformatics analysis revealed the presence of transcriptionally active or repressive intervals flanked by 6mA-enriched regions and results from chromatin conformation capture (3C) experiments suggest these 6mA flanked regions are in close spatial proximity. This finding revealed a new role for 6mA in modulating 3D chromatin structure and gene expression in this parasite. Based on these antecedents we now propose that 6mA could be a key regulator of 3D genome architecture by modulating expression of transcriptional- modules of genes during parasite infection. Three-dimensional arrangement of DNA in the nucleus are increasingly seen as key contributors to the regulation of gene expression but studies on how genome structure and nuclear organization influence transcription have so far been limited to a handful of model species. Guided by strong preliminary data, we propose to pursue three specific aims to further analyze the role of 6mA in the regulation of 3D genome conformation and gene expression during the process of parasite attachment to host cells. These results will provide new insights into T. vaginalis epigenetic regulation that may help to understand the mechanisms that lead to parasite adherence and cytotoxicity; key steps toward dissecting the specific outcomes of Trichomonas infection. Importantly, the association of 6mA with chromatin looping is noteworthy because it points to a novel function for this epigenetic mark in eukaryotes with scarce 5mC levels. 1

阴道毛滴虫宿主DNA甲基化、3D基因组结构和基因表达 相互作用 摘要 阴道毛滴虫是一种常见的性传播寄生虫，定殖人类泌尿生殖道 导致从无症状到高度炎症的感染。慢性感染可导致 严重的并发症，如不孕症，怀孕期间早产，增加了获得的风险 艾滋病，宫颈癌和侵袭性前列腺癌。因此，了解感染的过程是如何在 毛滴虫的寄生调控一直是寄生虫学研究和人类健康的重要目标。 宿主与寄生虫之间的相互作用受基因表达变化的调控，但其机制仍不清楚。 转录谱的这些变化受到控制，因为很少有转录调控元件 被描述。我们最近的工作强调了表观遗传学在调节 转录和寄生虫发病机制中的可能作用。具体来说，我们分析了 甲基化表明N6-甲基腺嘌呤（6mA）而不是5-甲基胞嘧啶（5mC）是主要的DNA 甲基化标记。流浪汉6mA的全基因组分布表明，该标记在 基因间区域，具有对DNA转座因子的某些超家族的偏好。有趣的是， 生物信息学分析揭示了转录活性或抑制间隔的存在， 6mA富集区域和来自染色质构象捕获（3C）实验的结果表明， 6mA侧翼区域在空间上非常接近。这一发现揭示了6mA在调节 该寄生虫的3D染色质结构和基因表达。基于这些前提，我们现在提出 6mA可能通过调节转录因子的表达， 寄生虫感染过程中的基因模块。DNA在细胞核中的三维排列是 越来越多地被视为基因表达调控的关键贡献者， 结构和核组织影响转录迄今为止仅限于少数几个模型 物种在强有力的初步数据的指导下，我们建议追求三个具体目标，以进一步分析 6mA在基因组三维构象和基因表达调控中的作用 寄生虫附着在宿主细胞上这些结果将为T.迷走神经后生的 可能有助于理解导致寄生虫粘附和细胞毒性的机制的调节; 对解剖毛滴虫感染的具体结果的关键步骤。重要的是， 6mA与染色质成环是值得注意的，因为它指出了一个新的功能，这种表观遗传标记， 真核生物中缺乏5mC水平。 1