Comparative three-dimensional genome architectures of adipose tissues provide insight into human-specific regulation of metabolic homeostasis

Elucidating the regulatory mechanisms of human adipose tis-sues (ATs) evolution is essential for understanding human-specific metabolic regulation, but the functional importance and evolu-tionary dynamics of three-dimensional (3D) genome organiza-tions of ATs are not well defined. Here, we compared the 3D genome architectures of anatomically distinct ATs from humans and six representative mammalian models. We recognized evolutionarily conserved and human-specific chromatin confor-mation in ATs at multiple scales, including compartmentalization, topologically associating domain (TAD), and promoter-enhancer interactions (PEI), which have not been described previously. We found PEI are much more evolutionarily dynamic with respect to compartmentalization and topologically associating domain. Compared to conserved PEIs, human-specific PEIs are enriched for human-specific sequence, and the binding motifs of their po-tential mediators (transcription factors) are less conserved. Our data also demonstrated that genes involved in the evolutionary dynamics of chromatin organization have weaker transcriptional conservation than those associated with conserved chromatin organization. Furthermore, the genes involved in energy meta-bolism and the maintenance of metabolic homeostasis are enriched in human-specific chromatin organization, while housekeeping genes, health-related genes, and genetic variations are enriched in evolutionarily conserved compared to human -specific chromatin organization. Finally, we showed extensively divergent human-specific 3D genome organizations among one subcutaneous and three visceral ATs. Together, these findings provide a global overview of 3D genome architecture dynamics between ATs from human and mammalian models and new in-sights into understanding the regulatory evolution of human ATs.

Automated summary

This study elucidates the dynamics of 3D genome architecture in human adipose tissues (ATs) and the differences compared to mammalian models. The researchers found evolutionarily conserved and human-specific chromatin conformations in ATs, with human-specific conformations enriched for human-specific sequence and less conserved transcription factor binding motifs. Genes associated with conserved chromatin organization exhibit higher transcriptional conservation, while those involved in the evolutionary dynamics of chromatin organization have lower transcriptional conservation. Additionally, human-specific chromatin organization is enriched for genes involved in energy metabolism and the maintenance of metabolic homeostasis, while evolutionarily conserved chromatin organization is enriched for genes related to basic physiological functions, health, and genetic variations.