Reorganization of 3D Genome Structure May Contribute to Gene Regulatory Evolution in Primates

A growing body of evidence supports the notion that variation in gene regulation plays a crucial role in speciation and adaptation. However, a comprehensive functional understanding of the mechanisms underlying regulatory evolution remains elusive. In primates, one of the crucial missing pieces of information towards a better understanding of regulatory evolution is a comparative annotation of interactions between distal regulatory elements and promoters. We used Hi-C to characterize 3D regulatory interactions in induced pluripotent stem cells (iPSCs) from humans and chimpanzees (Pan troglodytes). We overlaid these data with previously-collected RNA-seq data from the same cell lines. Generally, we observe that fine-scale distal 3D genomic interactions are conserved in humans and chimpanzees, but higher order genomic organization of contacts, such as TADs, are not as conserved. Inter-species differences in fine-scale 3D locus-locus interactions are often associated with gene expression differences between the species. To provide additional functional context to our observations, we also considered previously published chromatin data from human iPSCs. We found strong enrichment for both active and repressive marks in distal 3D genomic interactions that are both divergent between species and that are associated with inter-species differences in gene expression. Overall, our data demonstrates that, as expected, an understanding of 3D genome reorganization is key to explaining regulatory evolution. Examination of Hi-C contacts in 4 individual iPSC lines from humans and 4 individual iPSC lines from chimpanzees (both sex balanced).

越来越多的研究证据支持这一论点：基因调控变异在物种形成与适应性演化中发挥着至关重要的作用。然而，学界对调控进化背后机制的全面功能认知仍未明晰。在灵长类动物中，要更好地理解调控进化，关键缺失的信息之一便是远端调控元件与启动子之间相互作用的比较注释。我们采用Hi-C技术对人类与黑猩猩（Pan troglodytes）的诱导多能干细胞（induced pluripotent stem cells，iPSCs）中的三维调控相互作用进行了表征。我们将这些数据与此前在相同细胞系中获取的RNA测序（RNA-seq）数据进行了整合分析。总体而言，我们观察到人类与黑猩猩间的精细尺度远端三维基因组相互作用较为保守，但诸如拓扑关联结构域（Topologically Associating Domains，TADs）这类更高阶的基因组接触组织方式则保守性较弱。物种间的精细尺度三维基因座-基因座相互作用差异，往往与物种间的基因表达差异相关联。为了为我们的观测结果提供额外的功能背景，我们还分析了此前已发表的人类诱导多能干细胞染色质数据。我们发现，在兼具物种间差异性且与物种间基因表达差异相关的远端三维基因组相互作用中，活性与抑制性染色质修饰标记均呈现显著富集。总体而言，我们的数据证实：正如预期那般，对三维基因组重构的理解是解释调控进化的关键所在。本研究对4株来自不同个体的人类诱导多能干细胞、以及4株来自不同个体的黑猩猩诱导多能干细胞（均为性别平衡株系）的Hi-C接触数据进行了分析。