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

Background 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. Results 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. Conclusions Single-nucleus ATAC-seq combined with data-driven statistical analysis help elucidate the global gene regulation in vivo as a combination of modules and discover core genes of the relevant biological processes. ### Competing Interest Statement The authors have declared no competing interest. * GS : gene set IDF : inverse document frequency NAFL : non-alcoholic fatty liver NAFLD : non-alcoholic fatty liver disease NASH : non-alcoholic steatohepatitis snATAC-seq : single-nucleus ATAC-seq SVD : singular value decomposition TF : transcription factor