Gene regulation modules in non-alcoholic fatty liver disease revealed by single-nucleus ATAC-seq

Abstract

Non-alcoholic fatty liver disease (NAFLD) develops from fatty liver to steatohepatitis during which multiple cell types may play different roles. Aiming to understand tissue composition of cell types, their gene expression and global gene regulation in the development of NAFLD, we performed single-nucleus and bulk ATAC-seq on the liver of rats fed with a high-fat diet. By machine learning, we divided global gene expression into modules, such that transcription factors in a module regulate a set of genes in the same module. Consequently, many of the modules rediscovered known regulatory relationship between the transcription factors and biological processes. For the discovered biological processes, we searched core genes, which were defined as genes central regarding co-expression and protein-protein interaction. A large part of the core genes overlapped with previously implicated NAFLD genes. Our statistical methods help elucidate the global gene regulation in vivo as a combination of modules and discover core genes of the relevant biological processes.