Single-nucleus ATAC-seq elucidates major modules of gene regulation in the development of non-alcoholic fatty liver disease

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