Comparative 3D Genome Architectures of Adipose Tissues Provide Insight into Human-specific Regulation of Metabolic Homeostasis

Elucidating the regulatory mechanisms of human adipose tissue (AT) evolution is essential for understanding human metabolic homeostasis. In this study, we compared the chromatin architectures of anatomically distinct ATs from humans and six representative mammalian models. We recognized evolutionarily conserved and human-specific chromatin conformation at multiple scales, including compartmentalization, topologically associating domain (TAD), and promoter-enhancer interactions (PEI). We found PEIs are more evolutionarily dynamic with respect to compartmentalization and TAD. Human-specific chromatin structure-related genes were involved in multiple biological processes, including energy metabolism and maintenance of metabolic homeostasis. The genes regulated by human-specific PEIs were depleted for diabetic variations, implying a beneficial role in metabolic homeostasis. Additionally, numerous human-specific chromatin structures were observed among subcutaneous and visceral ATs, indicating the diversified functions of ATs during evolution. Collectively, the presented data highlight the value of comparative 3D genome analyses in dissecting the regulatory mechanisms of different ATs and evolution. To interrogate 3D genome organization of ATs in an evolutionary framework, we profiled the chromatin architectures through in situ high-throughput chromatin conformation capture (Hi-C) and profiled the transcriptome through rRNA-depleted RNA-seq for SATs collected from human and other six mammalian models (2-3 biological replicates for each mammal), including rodents (mouse and rat), lagomorphs (rabbit), carnivores (dog) and artiodactylids (pig and sheep), and three representative VATs (i.e., greater omentum [GOM], mesenteric adipose [MAD] and retroperitoneal adipose [RAD]) from human, pig and sheep (3 biological replicates for each VAT of each mammal).