Reorganization of 3D genome structure may contribute to gene regulatory evolution in primates

摘要

A growing body of evidence supports the notion that variation in gene regulation plays a crucial role in both 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. Chromatin conformation capture technologies have enabled genome-wide quantifications of such distal 3D interactions. However, relatively little comparative research in primates has been done using such technologies. To address this gap, we used Hi-C to characterize 3D chromatin interactions in induced pluripotent stem cells (iPSCs) from humans and chimpanzees. We also used RNA-seq to collect gene expression data from the same lines. We generally observed that lower-order, pairwise 3D genomic interactions are conserved in humans and chimpanzees, but higher order genomic structures, such as topologically associating domains (TADs), are not as conserved. Inter-species differences in 3D genomic interactions are often associated with gene expression differences between the species. To provide additional functional context to our observations, we considered previously published chromatin data from human stem cells. We found that inter-species differences in 3D genomic interactions, which are also associated with gene expression differences between the species, are enriched for both active and repressive marks. Overall, our data demonstrate that, as expected, an understanding of 3D genome reorganization is key to explaining regulatory evolution. Author summary The way in which a genome folds affects the regulation of gene expression. This is often due to loops in the three-dimensional structure that bring linearly distant genes and regulatory elements into close proximity. Most studies examining three-dimensional structure genome-wide are limited to a single species. In this study, we compared three-dimensional structure in the genomes of induced pluripotent stem cells from humans and chimpanzees. We collected gene expression data from the same samples, which allowed us to assess the contribution of three-dimensional chromatin conformation to gene regulatory evolution in primates. Our results demonstrate that gene expression differences between the species may often be mediated by differences in three-dimensional genomic interactions. Our data also suggest that large-scale chromatin structures (i.e. topologically associating domains, TADs) are not well conserved in their placement across species. We hope the analytical paradigms we present here could serve as a basis for future comparative studies of three-dimensional genome organization, elucidating the putative functional regulatory loci driving speciation.