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Oct4 and LIF/Stat3 additively induce Krüppel factors to sustain embryonic stem cell self-renewal.

TitleOct4 and LIF/Stat3 additively induce Krüppel factors to sustain embryonic stem cell self-renewal.
Publication TypeJournal Article
Year of Publication2009
AuthorsHall J, Guo G, Wray J, Eyres I, Nichols J, Grotewold L, Morfopoulou S, Humphreys P, Mansfield W, Walker R, Tomlinson SR, Smith A
JournalCell Stem Cell
Volume5
Issue6
Pagination597-609
Date Published2009 Dec 4
ISSN1875-9777
KeywordsAnimals, Bone Morphogenetic Protein 4, Cell Dedifferentiation, Cell Differentiation, Cell Proliferation, Cells, Cultured, Chimera, Gene Expression Regulation, Developmental, Humans, Induced Pluripotent Stem Cells, Kruppel-Like Transcription Factors, Leukemia Inhibitory Factor, Mice, Microarray Analysis, Octamer Transcription Factor-3, STAT3 Transcription Factor, Transcriptional Activation
Abstract

Embryonic stem cell (ESC) pluripotency is dependent on an intrinsic gene regulatory network centered on Oct4. Propagation of the pluripotent state is stimulated by the cytokine leukemia inhibitory factor (LIF) acting through the transcriptional regulator Stat3. Here, we show that this extrinsic stimulus converges with the intrinsic circuitry in Krüppel-factor activation. Oct4 primarily induces Klf2 while LIF/Stat3 selectively enhances Klf4 expression. Overexpression of either factor reduces LIF dependence, but with quantitative and qualitative differences. Unlike Klf4, Klf2 increases ESC clonogenicity, maintains undifferentiated ESCs in the genetic absence of Stat3, and confers resistance to BMP-induced differentiation. ESCs expanded with Klf2 remain capable of contributing to adult chimeras. Postimplantation-embryo-derived EpiSCs lack both Klf2 and Klf4 and expression of either can reinstate naive pluripotency. These findings indicate that Oct4 and Stat3 intersect in directing expression of Klf transcriptional regulators with overlapping properties that additively reinforce ground-state ESC pluripotency, identity, and self-renewal.

DOI10.1016/j.stem.2009.11.003
Alternate JournalCell Stem Cell
PubMed ID19951688
Grant ListG0700665 / / Medical Research Council / United Kingdom
G9806702 / / Medical Research Council / United Kingdom
/ / Biotechnology and Biological Sciences Research Council / United Kingdom
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom