title: Sumoylation of Krüppel-like factor 4 inhibits pluripotency induction but promotes adipocyte differentiation.
abstract: Ectopic expression of transcription factors has been shown to reprogram somatic cells into induced pluripotent stem (iPS) cells. It remains largely unexplored how this process is regulated by post-translational modifications. Several reprogramming factors possess conserved sumoylation sites, so we investigated whether and how this modification regulates reprogramming of fibroblasts into iPS cells. Substitution of the sole sumoylation site of the Krüppel-like factor (KLF4), a well known reprogramming factor, promoted iPS cell formation. In comparison, much smaller effects on reprogramming were observed for sumoylation-deficient mutants of SOX2 and OCT4, two other classical reprogramming factors. We also analyzed KLF2, a KLF4 homolog and a member of the KLF family of transcription factors with a known role in reprogramming. KLF2 was sumoylated at two conserved neighboring motifs, but substitution of the key lysine residues only stimulated reprogramming slightly. KLF5 is another KLF member with an established link to embryonic stem cell pluripotency. Interestingly, although it was much more efficiently sumoylated than either KLF2 or KLF4, KLF5 was inactive in reprogramming, and its sumoylation was not responsible for this deficiency. Furthermore, sumoylation of KLF4 but not KLF2 or KLF5 stimulated adipocyte differentiation. These results thus demonstrate the importance KLF4 sumoylation in regulating pluripotency and adipocyte differentiation.
authors.affiliation: Department of Anatomy and Cell Biology, McGill University Health Center, Montréal, Québec H3A 1A3, Canada.
authors.forename: Soroush
authors.initials: S
authors.lastname: Tahmasebi
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ghorbani
authors.forename: Paul
authors.initials: P
authors.lastname: Savage
authors.forename: Kezhi
authors.initials: K
authors.lastname: Yan
authors.forename: Goran
authors.initials: G
authors.lastname: Gocevski
authors.forename: Lin
authors.initials: L
authors.lastname: Xiao
authors.forename: Linya
authors.initials: L
authors.lastname: You
authors.forename: Xiang-Jiao
authors.initials: XJ
authors.lastname: Yang
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D058207:Sumoylation
chemical_list: C096161:KLF2 protein, human; C000715467:KLF4 protein, human; C492214:KLF5 protein, human; C498314:Klf2 protein, mouse; C000715468:Klf4 protein, mouse; C118391:Klf5 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C494174:Pou5f1 protein, mouse; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse
keywords: Adipocyte; Cell Differentiation; KLF2; KLF4; KLF5; Reprogramming; Sumoylation; Transcription Factors; iPS Cells