Dynamic remodeling of mRNA splicing and translation programs drives hepatocyte proliferation during liver regeneration

During liver regeneration, most new hepatocytes arise from pre-existing ones; yet, the underlying mechanisms that drive these cells from quiescence to proliferation remain poorly defined. By using high-resolution transcriptome profiling of purified hepatocytes isolated from quiescent and toxin-injured adult mouse livers,we uncover an overlap of regenerative response with developmental transcriptome programming. The translational remodeling modulates protein levels ofa set of splicing factors including Epithelial splicing regulatory protein 2 (ESRP2), which activates an early postnatal splicing program in regenerating hepatocytes. We find that regeneration-regulated exons are enriched within unstructured regions of proteins and frequently harbor amino-acid residues that can be post-translationally modified to influence protein-protein interactions. Hepatocytes were isolated from normal fed mice and DDC fed (4 week) mice. Additionally, hepatocytes were isolated from E18 livers wherein livers from approx. 8 E18 embryos were pooled to prepeare hepatocytes. From all samples total RNA was isolated and after polyA selection sequenced on an Illumina platform.