Dynamic remodeling of mRNA splicing and translation programs drives hepatocyte proliferation during liver regeneration. 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. Overall design: 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.