Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China.
Animal Genomics and Improvement Laboratory, Agricultural Research Service, USDA, Beltsville, MD, 20705, USA.
BMC Biol. 2020 Jul 6;18(1):85. doi: 10.1186/s12915-020-00793-5.
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.
改善动物健康并了解生产的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。尽管在人类和其他模式生物中已经对 DNA 甲基化进行了广泛的研究，但在牛中的分布模式和调控影响仍在很大程度上未知。在这里，我们提供了迄今为止最大的牛 DNA 甲基化表观基因组数据集。
我们使用荷斯坦牛生成了 16 种组织的 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进行了读映射和 DNA 甲基化调用，这表明基于长读长的组装显着提高了 DNA 甲基化结果的质量。我们观察到牛组织之间的全局 CpG 位点、部分甲基化域（PMD）、低甲基化区域（HMR）、CG 岛（CGI）和常见重复的甲基化模式存在很大差异。我们检测到每个组织都有一组独特的 PMD，这些 PMD 表现出组织特异性的模式。与人类 PMD 类似，牛 PMD 通常与基因表达普遍下降以及活性组蛋白标记下降有关，并与长程染色质组织有关，例如拓扑关联域（TAD）。我们基于相对于转录起始位点（TSS）的分布测试了 HMR 的分类，并检测到组织特异性 TSS-HMR 和表现出强烈组织效应的基因。当对配对基因（两个具有相同 TSS 的相反链基因，位于相同的 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、猪和鸡之间的表达更为一致，但在更为分化的物种中则表现出较低的一致性比例。我们进一步使用这些 WGBS 数据检测了牛组织中的 50,023 个实验支持的 CGI，并发现它们可能起到防止 TSS-HMR 中 C 到 T 突变的作用。尽管常见的重复通常被高度甲基化，但一些年轻的 Bov-A2 重复在精子中被低甲基化，并且可以通过暴露潜在的转录因子结合位点来影响启动子结构。
本研究为牛表观基因组学研究提供了一个全面的资源，并为 DNA 甲基化及其在复杂性状中的作用提供了新的发现。
