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Nat Struct Mol Biol. 2018 Oct;25(10):928-939. doi: 10.1038/s41594-018-0129-2. Epub 2018 Sep 24.

Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration.

Author information

1
Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
2
Departments of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3
Department of Molecular & Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
4
Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA. kalsotra@illinois.edu.
5
Carl R. Woese Institute of Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA. kalsotra@illinois.edu.

Abstract

During liver regeneration, most new hepatocytes arise via self-duplication; yet, the underlying mechanisms that drive hepatocyte proliferation following injury remain poorly defined. By combining high-resolution transcriptome and polysome profiling of hepatocytes purified from quiescent and toxin-injured mouse livers, we uncover pervasive alterations in messenger RNA translation of metabolic and RNA-processing factors, which modulate the protein levels of a set of splicing regulators. Specifically, downregulation of the splicing regulator ESRP2 activates a neonatal alternative splicing program that rewires the Hippo signaling pathway in regenerating hepatocytes. We show that production of neonatal splice isoforms attenuates Hippo signaling, enables greater transcriptional activation of downstream target genes, and facilitates liver regeneration. We further demonstrate that ESRP2 deletion in mice causes excessive hepatocyte proliferation upon injury, whereas forced expression of ESRP2 inhibits proliferation by suppressing the expression of neonatal Hippo pathway isoforms. Thus, our findings reveal an alternative splicing axis that supports regeneration following chronic liver injury.

PMID:
30250226
PMCID:
PMC6173981
[Available on 2019-03-24]
DOI:
10.1038/s41594-018-0129-2

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