3D genome organization under extreme metabolic adaptation shows variations in genome compartmentalization and looping

Three-dimensional (3D) genome organization plays a crucial role in gene regulation by influencing cellular functions, such as bringing regulatory elements like enhancers into proximity with their target genes. In this study, we explore variations in 3D genome organization within different morphs of the fish Astyanax mexicanus , which includes a river-dwelling surface fish and multiple cave-dwelling morphs. The cave morphs, also known as cavefish, have adapted to the dark and nutrient-scarce cave environments, resulting in distinct metabolic reprogramming that has made them persistently hyperglycemic, resilient to starvation, and prone to fat accumulation. Focusing on metabolic evolution in cavefish, we used liver tissue to conduct genome-wide contact mapping through Hi-C experiments. Comparing the 3D genome architecture of two cave morphs – Pachón and Tinaja – with that of surface fish, we observed significant changes in genome compartmentalization and genomic loops. Some of these changes were common in both Pachón and Tinaja and were classified as cave-specific looping and compartmental switches. By integrating liver Hi-C data with RNA-seq, ATAC-seq, and histone ChIP-seq datasets, we gained deeper insight into the relationship between cave-specific 3D genome features and the transcriptional activity at associated loci. Additionally, we identified structural variations in the form of common genomic inversions in Pachón and Tinaja compared to surface fish. Therefore, this study is the first to define the 3D genome organization of Astyanax mexicanus in livers and highlights how adaptation to extreme environments is associated with significant variations in 3D genome architecture, even within the same species.