title: ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation.
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.
authors.affiliation: Department of Biochemistry and Medical Biochemistry, University of Illinois, Champaign, Illinois 61801, USA.
authors.forename: Amruta
authors.initials: A
authors.lastname: Bhate
authors.affiliation: Department of Biochemistry and Medical Biochemistry, University of Illinois, Champaign, Illinois 61801, USA.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Parker
authors.affiliation: Departments of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Bebee
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, California 90095-7246, USA.
authors.forename: Jaegyoon
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Department of Biochemistry and Medical Biochemistry, University of Illinois, Champaign, Illinois 61801, USA.
authors.forename: Waqar
authors.initials: W
authors.lastname: Arif
authors.affiliation: Department of Biochemistry and Medical Biochemistry, University of Illinois, Champaign, Illinois 61801, USA.
authors.forename: Edrees H
authors.initials: EH
authors.lastname: Rashan
authors.affiliation: Department of Biochemistry and Medical Biochemistry, University of Illinois, Champaign, Illinois 61801, USA.
authors.forename: Sandip
authors.initials: S
authors.lastname: Chorghade
authors.affiliation: Department of Biochemistry and Medical Biochemistry, University of Illinois, Champaign, Illinois 61801, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Chau
authors.affiliation: Departments of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois, Champaign, Illinois 61801, USA.
authors.forename: Sayeepriyadarshini
authors.initials: S
authors.lastname: Anakk
authors.affiliation: Departments of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Russ P
authors.initials: RP
authors.lastname: Carstens
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, California 90095-7246, USA.
authors.forename: Xinshu
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Biochemistry and Medical Biochemistry, University of Illinois, Champaign, Illinois 61801, USA.|Carl R. Woese Institute of Genomic Biology, University of Illinois, Champaign, Illinois 61801, USA.
authors.forename: Auinash
authors.identifier: http://orcid.org/0000-0002-1011-0006
authors.initials: A
authors.lastname: Kalsotra
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D018507:Gene Expression Regulation, Developmental; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008099:Liver / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C539365:ESRP2 protein, human; C000607388:ESRP2 protein, mouse; D020033:Protein Isoforms; D016601:RNA-Binding Proteins