Xiang Guanjue, He Xi, Giardine Belinda M, Isaac Kathryn J, Taylor Dylan J, McCoy Rajiv C, Jansen Camden, Keller Cheryl A, Wixom Alexander Q, Cockburn April, Miller Amber, Qi Qian, He Yanghua, Li Yichao, Lichtenberg Jens, Heuston Elisabeth F, Anderson Stacie M, Luan Jing, Vermunt Marit W, Yue Feng, Sauria Michael E G, Schatz Michael C, Taylor James, Gottgens Berthold, Hughes Jim R, Higgs Douglas R, Weiss Mitchell J, Cheng Yong, Blobel Gerd A, Bodine David M, Zhang Yu, Li Qunhua, Mahony Shaun, Hardison Ross C
bioRxiv. 2024 May 17:2023.04.02.535219. doi: 10.1101/2023.04.02.535219.
Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state Regulatory Potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbored distinctive transcription factor binding motifs that were similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we showed that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.
为了解基因调控的基本机制并理解遗传变异对复杂性状的影响，需要了解顺式调控元件（CRE）的位置和活性。以往的研究利用一个物种的表观遗传特征来识别候选CRE（cCRE），这使得不同物种之间难以进行比较。相比之下，我们在“验证系统整合（VISION）项目”中，通过对人类和小鼠的八种表观遗传特征进行综合建模，开展了一项跨物种研究，定义表观遗传状态并在血细胞类型中识别cCRE，以生成不同物种间可比的调控图谱。所得的cCRE目录是进一步研究血细胞基因调控的有用资源，这体现在与已知功能元件的高度重叠以及与血细胞表型相关的人类遗传变异的强烈富集上。从多变量回归推断出的cCRE中每种表观遗传状态对基因调控的贡献，用于估计每种细胞类型中每个cCRE的表观遗传状态调控潜力（esRP）分数，这些分数用于对cCRE的动态变化进行分类。通过对esRP分数进行联合聚类，在人类和小鼠细胞类型中显示出相似调控活性模式的cCRE组，含有物种间相似的独特转录因子结合基序。对cCRE的跨物种比较揭示了表观遗传进化的保守和物种特异性模式。最后，我们表明，即使在没有基因组序列比对的情况下，物种间表观遗传景观的比较也可以揭示在调控中具有相似作用的元件。
