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Reduced Oct4 expression directs a robust pluripotent state with distinct signaling activity and increased enhancer occupancy by Oct4 and Nanog.

TitleReduced Oct4 expression directs a robust pluripotent state with distinct signaling activity and increased enhancer occupancy by Oct4 and Nanog.
Publication TypeJournal Article
Year of Publication2013
AuthorsKarwacki-Neisius V, Göke J, Osorno R, Halbritter F, Ng JHui, Weiße AY, Wong F, Gagliardi A, Mullin NP, Festuccia N, Colby D, Tomlinson SR, Ng H-H, Chambers I
JournalCell Stem Cell
Volume12
Issue5
Pagination531-45
Date Published2013 May 2
ISSN1875-9777
KeywordsBase Sequence, Bone Morphogenetic Proteins, Cell Differentiation, Cell Proliferation, Clone Cells, Embryonic Stem Cells, Enhancer Elements, Genetic, Homeodomain Proteins, Humans, Molecular Sequence Data, Octamer Transcription Factor-3, Pluripotent Stem Cells, Protein Binding, Serum, Signal Transduction, Wnt Proteins
Abstract

Embryonic stem cell (ESC) pluripotency is governed by a gene regulatory network centered on the transcription factors Oct4 and Nanog. To date, robust self-renewing ESC states have only been obtained through the chemical inhibition of signaling pathways or enforced transgene expression. Here, we show that ESCs with reduced Oct4 expression resulting from heterozygosity also exhibit a stabilized pluripotent state. Despite having reduced Oct4 expression, Oct4(+/-) ESCs show increased genome-wide binding of Oct4, particularly at pluripotency-associated enhancers, homogeneous expression of pluripotency transcription factors, enhanced self-renewal efficiency, and delayed differentiation kinetics. Cells also exhibit increased Wnt expression, enhanced leukemia inhibitory factor (LIF) sensitivity, and reduced responsiveness to fibroblast growth factor. Although they are able to maintain pluripotency in the absence of bone morphogenetic protein, removal of LIF destabilizes pluripotency. Our findings suggest that cells with a reduced Oct4 concentration range are maintained in a robust pluripotent state and that the wild-type Oct4 concentration range enables effective differentiation.

DOI10.1016/j.stem.2013.04.023
Alternate JournalCell Stem Cell
PubMed ID23642364
PubMed Central IDPMC3650585
Grant List / / Biotechnology and Biological Sciences Research Council / United Kingdom
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom