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Nat Commun. 2015 Nov 4;6:8768. doi: 10.1038/ncomms9768.

ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation.

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Department of Biochemistry and Medical Biochemistry, University of Illinois, Champaign, Illinois 61801, USA.
Departments of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Department of Integrative Biology and Physiology, University of California, Los Angeles, California 90095-7246, USA.
Department of Molecular and Integrative Physiology, University of Illinois, Champaign, Illinois 61801, USA.
Carl R. Woese Institute of Genomic Biology, University of Illinois, Champaign, Illinois 61801, USA.


Although major genetic networks controlling early liver specification and morphogenesis are known, the mechanisms responsible for postnatal hepatic maturation are poorly understood. Here we employ global analyses of the mouse liver transcriptome to demonstrate that postnatal remodelling of the liver is accompanied by large-scale transcriptional and post-transcriptional transitions that are cell-type-specific and temporally coordinated. Combining detailed expression analyses with gain- and loss-of-function studies, we identify epithelial splicing regulatory protein 2 (ESRP2) as a conserved regulatory factor that controls the neonatal-to-adult switch of ∼20% of splice isoforms in mouse and human hepatocytes. The normal shift in splicing coincides tightly with dramatic postnatal induction of ESRP2 in hepatocytes. We further demonstrate that forced expression of ESRP2 in immature mouse and human hepatocytes is sufficient to drive a reciprocal shift in splicing and causes various physiological abnormalities. These findings define a direct role for ESRP2 in the generation of conserved repertoires of adult splice isoforms that facilitate terminal differentiation and maturation of hepatocytes.

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