Zfx controls self-renewal of human embryonic stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Stuart Chambers
PROVIDER: E-GEOD-29784 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Previously, we identified the transcription factor Zfx as a key regulator of self-renewal in murine ESCs. Here we extend those findings to human ESCs. Zfx knockdown in hESCs hindered clonal growth and decreased colony size after serial replating. Zfx overexpression enhanced clone formation, increased colony size and decreased expression of differentiation-related genes in human ESCs. Zfx-overexpressing hESCs resisted spontaneous differentiation but could be directed to differentiate into endodermal and neural cell fates when provided with the appropriate cues. Thus, Zfx acts as a molecular rheostat regulating the balance between self-renewal and differentiation in hESCs, revealing the close evolutionary conservation of the self-renewal mechanisms in murine and human ESCs.
2012-01-01 | GSE29784 | GEO
Project description:Human ESCs are pluripotent cells that have the capacity of self renewal for a prolonged period in vitro, and can differentiate into derivatives of all three primary germ layers: endoderm, mesoderm and ectoderm. Human ESCs are responsive to a wide range of factors in vitro that can direct their differentiation into specific cell types. We analyzed the effect of nicotinamide (NIC) on differentiation of hESCs in vitro. CEL file for GSM424319 is unavailable. Experiment Overall Design: hESCs were cultured as free-floating clusters in the presence of 10% FCS for 4 weeks in the presence or absence of nicotinamide.
2009-10-09 | E-GEOD-16919 | biostudies-arrayexpress
Project description:Stem cells (SC) exhibit a unique capacity for self-renewal in an undifferentiated state. It is unclear whether the self-renewal of pluripotent embryonic SC (ESC) and of tissue-specific adult SC such as hematopoietic SC (HSC) is controlled by common mechanisms. The deletion of transcription factor Zfx impaired the self-renewal but not the differentiation capacity of murine ESC; conversely, Zfx overexpression facilitated ESC self-renewal by opposing differentiation. Furthermore, Zfx deletion abolished the maintenance of adult bone marrow HSC, but did not affect erythromyeloid progenitors or fetal HSC. In both ESC and HSC, Zfx activated a common set of direct target genes. In addition, the loss of Zfx resulted in the induction of immediate-early and/or stress-inducible genes in both SC types but not in their differentiated progeny. These studies identify the first shared transcriptional regulator of ESC and HSC, suggesting a common molecular basis of self-renewal in embryonic and adult SC. Keywords: Global gene expression data analysis in Zfx-deficient murine ESC and HSC
2007-04-20 | GSE7069 | GEO
Project description:The transcription factors Nanog, Oct4 and Sox2 are the master regulators of pluripotency in mouse embryonic stem cells (mESCs), however, their functions in human ESCs (hESCs) have not been rigorously defined. Here we show that the requirements for NANOG, OCT4 and SOX2 in hESCs differ from those in mESCs. Both NANOG and OCT4 are required for self-renewal and repress differentiation. OCT4 controls both extraembryonic and epiblast-derived cell fates in a BMP4-dependent manner. OCT4-depleted hESCs commit to trophectoderm and primitive endoderm in the presence of BMP4, but undergo neuroectoderm differentiation in the absence of BMP4. NANOG represses neuroectoderm and neural crest commitment, but has little or no effect on the other lineages. We find that SOX2 is not required for self-renewal because it is redundant with SOX3, which is induced in SOX2-depleted hESCs. Simultaneous depletion of both SOX2 and SOX3 induces differentiation into the primitive streak. Unexpectedly, we identify significant variability in the usage of pluripotency factors by individual hESC lines, suggesting that the pluripotency network is remodelled to support a continuum of developmental states. Our study revises the general view of how NANOG, OCT4 and SOX2 orchestrate self-renewal in hESCs. Total RNA obtained from EF1a-control-, OE-NANOG-, OE-OCT4- or OE-SOX2-transduced hESCs.
2012-04-05 | E-GEOD-34920 | biostudies-arrayexpress
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2012-04-05 | E-GEOD-34912 | biostudies-arrayexpress
Project description:The transcription factors Nanog, Oct4 and Sox2 are the master regulators of pluripotency in mouse embryonic stem cells (mESCs), however, their functions in human ESCs (hESCs) have not been rigorously defined. Here we show that the requirements for NANOG, OCT4 and SOX2 in hESCs differ from those in mESCs. Both NANOG and OCT4 are required for self-renewal and repress differentiation. OCT4 controls both extraembryonic and epiblast-derived cell fates in a BMP4-dependent manner. OCT4-depleted hESCs commit to trophectoderm and primitive endoderm in the presence of BMP4, but undergo neuroectoderm differentiation in the absence of BMP4. NANOG represses neuroectoderm and neural crest commitment, but has little or no effect on the other lineages. We find that SOX2 is not required for self-renewal because it is redundant with SOX3, which is induced in SOX2-depleted hESCs. Simultaneous depletion of both SOX2 and SOX3 induces differentiation into the primitive streak. Unexpectedly, we identify significant variability in the usage of pluripotency factors by individual hESC lines, suggesting that the pluripotency network is remodelled to support a continuum of developmental states. Our study revises the general view of how NANOG, OCT4 and SOX2 orchestrate self-renewal in hESCs. Total RNA obtained from SOX2-KD stable hESC clones and H1P control stable hESC clones.
2012-04-05 | E-GEOD-34918 | biostudies-arrayexpress
Project description:The transcription factors Nanog, Oct4 and Sox2 are the master regulators of pluripotency in mouse embryonic stem cells (mESCs), however, their functions in human ESCs (hESCs) have not been rigorously defined. Here we show that the requirements for NANOG, OCT4 and SOX2 in hESCs differ from those in mESCs. Both NANOG and OCT4 are required for self-renewal and repress differentiation. OCT4 controls both extraembryonic and epiblast-derived cell fates in a BMP4-dependent manner. OCT4-depleted hESCs commit to trophectoderm and primitive endoderm in the presence of BMP4, but undergo neuroectoderm differentiation in the absence of BMP4. NANOG represses neuroectoderm and neural crest commitment, but has little or no effect on the other lineages. We find that SOX2 is not required for self-renewal because it is redundant with SOX3, which is induced in SOX2-depleted hESCs. Simultaneous depletion of both SOX2 and SOX3 induces differentiation into the primitive streak. Unexpectedly, we identify significant variability in the usage of pluripotency factors by individual hESC lines, suggesting that the pluripotency network is remodelled to support a continuum of developmental states. Our study revises the general view of how NANOG, OCT4 and SOX2 orchestrate self-renewal in hESCs. Total RNA obtained from H1P (control)-, shNANOG (Nanog shRNA knockdown)-, shOCT4 (Oct4 shRNA knockdown)- or shSOX2 (Sox2 shRNA knockdown)-transduced hESCs for 8 days time course.
2012-04-05 | E-GEOD-34904 | biostudies-arrayexpress
Project description:Human ESCs are pluripotent cells that have the capacity of self renewal for a prolonged period in vitro, and can differentiate into derivatives of all three primary germ layers: endoderm, mesoderm and ectoderm. Human ESCs are responsive to a wide range of factors in vitro that can direct their differentiation into specific cell types. We analyzed the effect of nicotinamide (NIC) on differentiation of hESCs in vitro. CEL file for GSM424319 is unavailable.
2009-10-02 | GSE16919 | GEO
Project description:Long non-coding RNAs (lncRNAs) are recently characterized players that are involved in the regulatory circuitry of self-renewal in human embryonic stem cells (hESCs). However, the specific roles of lncRNAs in this circuitry are poorly understood. Here, we determined that growth-arrest-specific transcript 5 (GAS5), which is a known tumor suppressor and growth arrest gene, is abundantly expressed in the cytoplasm of hESCs and essential for hESC self-renewal. GAS5 depletion in hESCs significantly impaired their pluripotency and self-renewal ability, whereas GAS5 overexpression in hESCs accelerated the cell cycle, enhanced their colony formation ability and increased pluripotency marker expression. By RNA sequencing and bioinformatics analysis, we determined that GAS5 activates NODAL-SMAD2/3 signaling by sustaining the expression of NODAL, which plays a key role in hESC self-renewal but not in somatic cell growth. Further studies indicated that GAS5 functions as a competing endogenous RNA (ceRNA) to protect NODAL mRNA against degradation and that GAS5 transcription is directly controlled by the core pluripotency transcriptional factors (TFs). Taken together, we suggest that the core TFs, GAS5 and NODAL-SMAD2/3 form a feed-forward loop to maintain the hESC self-renewal process. These findings are specific to ESCs and did not occur in the somatic cell lines we tested; therefore, our findings also provide evidence that the functions of lncRNAs vary in different biological contexts.
2016-03-17 | GSE66993 | GEO
Project description:Calcineurin-NFAT signaling is associated with a wide range of biological processes and diseases. Our previous study showed that this pathway plays a critical role in mouse embryonic stem cell (mESC) differentiation. However, its function in human ESCs (hESCs) remains unclear. Here, we report that expression of PPP3CC, the gene encoding the catalytic subunit of calcineurin, increases along with the process of hESC differentiation, and its knockdown (KD) enhances the self-renewal ability of hESCs with a simultaneous reduction in the expression of differentiation-associated markers regardless of culture conditions. Moreover, we observed that NFATC3 translocates from the cytoplasm to the nucleus when hESCs exit from a self-renewal state. These results indicate that calcineurin-NFAT signaling is activated and required during hESC differentiation. Mechanistically, we also found that in hESCs NFATC3 interacts with JUN， one of AP-1 complex subunit, and co-expression of exogenous NFATC3 and JUN upregulates lineage markers remarkably even under a self-renewal culture condition. Additionally, inhibition of this cascade represses MAPK signaling rapidly, including ERK1/2, JNK and P38. Taken together, this study delineates the importance of the calcineurin-NFATC3/JUN signaling cascade for the pluripotency maintenance of hESCs.
2020-08-04 | GSE155563 | GEO