Talk on Friday 03:15-03:30pm submitted by Sushant Bangru
Dynamic remodeling of mRNA splicing and translation programs drives hepatocyte proliferation during liver regeneration.
Sushant Bangru (Dept. of Biochemistry, University of Illinois, Urbana-Champaign), Waqar Arif (Dept. of Biochemistry, University of Illinois, Urbana-Champaign), Joseph Seimetz, Amruta Bhate, Jackie Chen, Edrees Rashan (Dept. of Biochemistry, University of Illinois, Urbana-Champaign), Russ P. Carstens (Dept. of Medicine and Genetics, Perelman school of medicine, University of Pennsylvania), Sayeepriyadarshini Anakk (Dept. of Molecular and Integrative Physiology, University of Illinois, Urbana-Champaign), Auinash Kalsotra (Dept. of Biochemistry, and Carl R. Woese Institute of genomic biology at University of Illinois, Urbana-Champaign)
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 combining high-resolution transcriptome and polysome profiling of purified hepatocytes isolated from quiescent and toxin-injured adult mouse livers, we uncover a pervasive shift in ribosome occupancies for transcripts encoding metabolic and RNA processing factors. This translational remodeling modulates protein levels of a 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 rewire protein-protein interactions. Finally, we demonstrate that dynamic regulation of ESRP2 upon toxin-injury tunes hepatocyte proliferation by coordinating alternative splicing of core components of the Hippo signaling pathway. Altogether, our data reveal that after sustaining injury, an early postnatal splicing program is redeployed in adult hepatocytes, which reprograms critical signaling pathways to enable hepatocyte proliferation and proper liver regeneration.
Keywords: alternative splicing , liver regeneration, translational regulation