title: SUMOylation of HNF4α regulates protein stability and hepatocyte function.
abstract: The coordination of signalling pathways within the cell is vital for normal human development and post-natal tissue homeostasis. Gene expression and function is therefore tightly controlled at a number of levels. We investigated the role that post-translational modifications play during human hepatocyte differentiation. In particular, we examined the role of the small ubiquitin-like modifier (SUMO) proteins in this process. We used a human embryonic stem cell (hESC)-based model of hepatocyte differentiation to follow changes in protein SUMOylation. Moreover, to confirm the results derived from our cell-based system, we performed in vitro conjugation assays to characterise SUMO modification of a key liver-enriched transcription factor, HNF4α. Our analyses indicate that SUMOylation plays an important role during hepatocellular differentiation and this is mediated, in part, through regulation of the stability of HNF4α in a ubiquitin-dependent manner. Our study provides a better understanding of SUMOylation during human hepatocyte differentiation and maturation. Moreover, we believe the results will stimulate interest in the differentiation and phenotypic regulation of other somatic cell types.
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh Bio Quarter, 5 Little France Drive, Edinburgh EH16 4UU, UK.
authors.forename: Wenli
authors.initials: W
authors.lastname: Zhou
authors.forename: Zara
authors.initials: Z
authors.lastname: Hannoun
authors.forename: Ellis
authors.initials: E
authors.lastname: Jaffray
authors.forename: Claire N
authors.initials: CN
authors.lastname: Medine
authors.forename: James R
authors.initials: JR
authors.lastname: Black
authors.forename: Sebastian
authors.initials: S
authors.lastname: Greenhough
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.forename: James A
authors.initials: JA
authors.lastname: Ross
authors.forename: Stuart
authors.initials: S
authors.lastname: Forbes
authors.forename: Ian
authors.initials: I
authors.lastname: Wilmut
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Hay
authors.forename: David C
authors.initials: DC
authors.lastname: Hay
mesh_terms: D020134:Catalytic Domain; D002454:Cell Differentiation / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D055550:Protein Stability; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D058207:Sumoylation; D014157:Transcription Factors / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D009687:Nuclear Proteins; C114070:RNF4 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors