Efforts to improve animal health, and understand genetic bases for production, may benefit from a comprehensive analysis of animal genomes and epigenomes. Although DNA methylation has been well studied in humans and other model species, its distribution patterns and regulatory impacts in cattle are still largely unknown. Here, we present the largest collection of cattle DNA methylation epigenomic data to date. Using Holstein cattle, we generated 29 whole genome bisulfite sequencing (WGBS) datasets for 16 tissues, 47 corresponding RNA-seq datasets, and 2 whole genome sequencing datasets. We did read mapping and DNA methylation calling based on two different cattle assemblies, demonstrating the high quality of the long-read-based assembly markedly improved DNA methylation results. We observed large differences across cattle tissues in the methylation patterns of global CpG sites, partially methylated domains (PMDs), hypomethylated regions (HMRs), CG islands (CGIs), and common repeats. We detected that each tissue had a distinct set of PMDs, which showed tissue-specific patterns. Similar to human PMD, cattle PMDs were often linked to a general decrease of gene expression and a decrease in active histone marks and related to long-range chromatin organizations, like topologically associated domains (TADs). We tested a classification of the HMRs based on their distributions relative to transcription start sites (TSSs) and detected tissue-specific TSS-HMRs and genes that showed strong tissue effects. When performing cross-species comparisons of paired genes (two opposite strand genes with their TSS located in the same HMR), we found out they were more consistently co-expressed among human, mouse, sheep, goat, yak, pig, and chicken, but showed lower consistent ratios in more divergent species. We further used these WGBS data to detect 50,023 experimentally supported CGIs across bovine tissues and found that they might function as a guard against C-to-T mutations for TSS-HMRs. Although common repeats were often heavily methylated, some young Bov-A2 repeats were hypomethylated in sperm and could affect the promoter structures by exposing potential transcription factor binding sites. This study provides a comprehensive resource for bovine epigenomic research and enables new discoveries about DNA methylation and its role in complex traits.

中文翻译：

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跨牛组织的比较全基因组 DNA 甲基化谱揭示了整体和组织特异性甲基化模式。


改善动物健康和了解生产遗传基础的努力可能会受益于对动物基因组和表观基因组的全面分析。尽管 DNA 甲基化在人类和其他模型物种中已得到充分研究，但其在牛中的分布模式和调控影响仍然很大程度上未知。在这里，我们展示了迄今为止最大的牛 DNA 甲基化表观基因组数据集。使用荷斯坦牛，我们生成了 16 个组织的 29 个全基因组亚硫酸氢盐测序 (WGBS) 数据集、47 个相应的 RNA-seq 数据集和 2 个全基因组测序数据集。我们基于两个不同的牛组装体进行了读图谱和 DNA 甲基化调用，证明了基于长读长的组装的高质量显着改善了 DNA 甲基化结果。我们观察到牛组织中整体 CpG 位点、部分甲基化结构域 (PMD)、低甲基化区域 (HMR)、CG 岛 (CGI) 和常见重复序列的甲基化模式存在巨大差异。我们检测到每个组织都有一组不同的 PMD，显示出组织特异性模式。与人类 PMD 类似，牛 PMD 通常与基因表达的普遍下降和活性组蛋白标记的减少有关，并与长程染色质组织有关，例如拓扑相关结构域 (TAD)。我们根据 HMR 相对于转录起始位点 (TSS) 的分布测试了 HMR 的分类，并检测了组织特异性 TSS-HMR 和表现出强烈组织效应的基因。 当对配对基因（两个相反的链基因，其 TSS 位于同一 HMR 中）进行跨物种比较时，我们发现它们在人类、小鼠、绵羊、山羊、牦牛、猪和鸡中更一致地共表达，但在差异较大的物种中表现出较低的一致性比率。我们进一步使用这些 WGBS 数据检测了跨牛组织的 50,023 个实验支持的 CGI，并发现它们可能起到防范 TSS-HMR 的 C 到 T 突变的作用。尽管常见的重复序列通常高度甲基化，但一些年轻的 Bov-A2 重复序列在精子中甲基化程度较低，并且可能通过暴露潜在的转录因子结合位点来影响启动子结构。这项研究为牛表观基因组研究提供了全面的资源，并使有关 DNA 甲基化及其在复杂性状中的作用的新发现成为可能。