Miller Ryan H, Pollard Chad A, Brogaard Kristin R, Olson Andrew C, Barney Ryan C, Lipshultz Larry I, Johnstone Erica B, Ibrahim Yetunde O, Hotaling James M, Schisterman Enrique F, Mumford Sunni L, Aston Kenneth I, Jenkins Tim G
Inherent Biosciences, Salt Lake City, UT, United States.
Department of Cell Biology and Physiology, Brigham Young University, Provo, UT, United States.
Front Genet. 2023 Jul 19;14:1125967. doi: 10.3389/fgene.2023.1125967. eCollection 2023.
Complex diseases have multifactorial etiologies making actionable diagnostic biomarkers difficult to identify. Diagnostic research must expand beyond single or a handful of genetic or epigenetic targets for complex disease and explore a broader system of biological pathways. With the objective to develop a diagnostic tool designed to analyze a comprehensive network of epigenetic profiles in complex diseases, we used publicly available DNA methylation data from over 2,400 samples representing 20 cell types and various diseases. This tool, rather than detecting differentially methylated regions at specific genes, measures the intra-individual methylation variability within gene promoters to identify global shifts away from healthy regulatory states. To assess this new approach, we explored three distinct questions: 1) Are profiles of epigenetic variability tissue-specific? 2) Do diseased tissues exhibit altered epigenetic variability compared to normal tissue? 3) Can epigenetic variability be detected in complex disease? Unsupervised clustering established that global epigenetic variability in promoter regions is tissue-specific and promoter regions that are the most epigenetically stable in a specific tissue are associated with genes known to be essential for its function. Furthermore, analysis of epigenetic variability in these most stable regions distinguishes between diseased and normal tissue in multiple complex diseases. Finally, we demonstrate the clinical utility of this new tool in the assessment of a multifactorial condition, male infertility. We show that epigenetic variability in purified sperm is correlated with live birth outcomes in couples undergoing intrauterine insemination (IUI), a common fertility procedure. Men with the least epigenetically variable promoters were almost twice as likely to father a child than men with the greatest number of epigenetically variable promoters. Interestingly, no such difference was identified in men undergoing fertilization (IVF), another common fertility procedure, suggesting this as a treatment to overcome higher levels of epigenetic variability when trying to conceive.
复杂疾病具有多因素病因，使得难以确定可用于指导治疗的诊断生物标志物。对于复杂疾病的诊断研究必须超越单一或少数几个基因或表观遗传靶点，探索更广泛的生物通路系统。为了开发一种用于分析复杂疾病中表观遗传谱综合网络的诊断工具，我们使用了来自代表20种细胞类型和各种疾病的2400多个样本的公开可用DNA甲基化数据。该工具不是检测特定基因处的差异甲基化区域，而是测量基因启动子内个体甲基化变异性，以识别偏离健康调控状态的整体变化。为了评估这种新方法，我们探讨了三个不同的问题：1）表观遗传变异性谱是否具有组织特异性？2）与正常组织相比，患病组织的表观遗传变异性是否发生改变？3）能否在复杂疾病中检测到表观遗传变异性？无监督聚类表明，启动子区域的整体表观遗传变异性具有组织特异性，并且在特定组织中表观遗传最稳定的启动子区域与已知对其功能至关重要的基因相关。此外，对这些最稳定区域的表观遗传变异性分析能够区分多种复杂疾病中的患病组织和正常组织。最后，我们展示了这种新工具在评估多因素疾病男性不育症中的临床应用。我们发现，纯化精子中的表观遗传变异性与接受宫内人工授精（IUI，一种常见的生育程序）的夫妇的活产结局相关。启动子表观遗传变异性最小的男性生育孩子的可能性几乎是启动子表观遗传变异性最大的男性的两倍。有趣的是，在接受另一种常见生育程序体外受精（IVF）的男性中未发现这种差异，这表明这是一种在尝试受孕时克服较高表观遗传变异性水平的治疗方法。
