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

We investigated the progression of non-alcoholic fatty liver disease (NAFLD) from fatty liver to steatohepatitis using single-nucleus and bulk ATAC-seq on the livers of rats fed a high-fat diet (HFD). Rats fed HFD for 4 weeks developed fatty liver, and those fed HFD for 8 weeks further progressed to steatohepatitis. We observed an increase in the proportion of inflammatory macrophages, consistent with the pathological progression. Utilizing machine learning, we divided global gene regulation into modules, wherein transcription factors within a module could regulate genes within the same module, reaffirming known regulatory relationships between transcription factors and biological processes. We identified core genes--central to co-expression and protein-protein interaction--for the biological processes discovered. Notably, a large part of the core genes overlapped with genes previously implicated in NAFLD. Single-nucleus ATAC-seq, combined with data-driven statistical analysis, offers insight into in vivo global gene regulation as a combination of modules and assists in identifying core genes of relevant biological processes. Summary blurbThis study uncovers cell type-specific global gene regulation in NAFLD progression, identifying core genes and shedding light on the diseases molecular mechanisms.