Reduced Oct4 Expression Directs a Robust Pluripotent State with Distinct Signaling Activity and Increased Enhancer Occupancy by Oct4 and Nanog
نویسندگان
چکیده
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.
منابع مشابه
Oct4 shuffles Sox partners to direct cell fate.
The transcription factor Oct4 plays a crucial role in the maintenance of the embryonic pluripotent state, but can also regulate early lineage commitment. In this issue of The EMBO Journal, Aksoy et al (2013) lend critical mechanistic insights into the ability of Oct4 to regulate and specify the primitive endodermal lineage. These regulatory actions are governed by alternative direct partnering ...
متن کاملConcurrent Expression of Oct4 and Nanog Maintains Mesenchymal Stem-Like Property of Human Dental Pulp Cells
Human dental pulp stem cells (DPSCs), unique mesenchymal stem cells (MSCs) type, exhibit the characteristics of self-renewal and multi-lineage differentiation capacity. Oct4 and Nanog are pluripotent genes. The aim of this study was to determine the physiological functions of Oct4 and Nanog expression in DPSCs. Herein, we determined the critical role of an Oct4/Nanog axis modulating MSCs proper...
متن کاملThe Role of Wnt/β-catenin Signaling Pathway in Rat Primordial Germ Cells Reprogramming and Induction into Pluripotent State
Primordial Germ Cells (PGCs) are unipotent precursors of the gametes. PGCs can give rise to a type of pluripotent stem cells in vitro that are called embryonic germ (EG) cells. PGCs can also acquire such pluripotency in vivo and generate teratomas. Under specific culture conditions, PGCs can be reprogrammed to embryonic germ cells which are capable of expression of key pluripotency marker...
متن کاملDistinct Enhancer Activity of Oct4 in Naive and Primed Mouse Pluripotency
Naive and primed pluripotent stem cells (PSCs) and germ cells express the Oct4 gene. The Oct4 gene contains two cis-regulatory elements, the distal enhancer (DE) and proximal enhancer (PE), which differentially control Oct4 expression in a cell-type-specific and stage-specific manner. Here, we generated double transgenic mice carrying both Oct4-ΔPE-GFP and Oct4-ΔDE-tdTomato (RFP), enabling us t...
متن کاملRegulated Fluctuations in Nanog Expression Mediate Cell Fate Decisions in Embryonic Stem Cells
There is evidence that pluripotency of mouse embryonic stem (ES) cells is associated with the activity of a network of transcription factors with Sox2, Oct4, and Nanog at the core. Using fluorescent reporters for the expression of Nanog, we observed that a population of ES cells is best described by a dynamic distribution of Nanog expression characterized by two peaks defined by high (HN) and l...
متن کامل