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

Amruta Bhate, Darren J. Parker, Thomas W. Bebee, Jaegyoon Ahn, Waqar Arif, Edrees H. Rashan, Sandip Chorghade, Anthony Chau, Jae-Hyung Lee, Sayeepriyadarshini Anakk, Russ P. Carstens, Xinshu Xiao and Auinash Kalsotra ()
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Amruta Bhate: University of Illinois
Darren J. Parker: University of Illinois
Thomas W. Bebee: Perelman School of Medicine, University of Pennsylvania
Jaegyoon Ahn: University of California
Waqar Arif: University of Illinois
Edrees H. Rashan: University of Illinois
Sandip Chorghade: University of Illinois
Anthony Chau: University of Illinois
Jae-Hyung Lee: Perelman School of Medicine, University of Pennsylvania
Sayeepriyadarshini Anakk: University of Illinois
Russ P. Carstens: Perelman School of Medicine, University of Pennsylvania
Xinshu Xiao: University of California
Auinash Kalsotra: University of Illinois

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms9768

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