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Primary cilium-autophagy-Nrf2 (PAN) axis links the cell cycle to neuroectoderm fate in human embryonic stem cells

ABSTRACT: Under defined differentiation conditions human embryonic stem cells (hESCs) can be directed toward a mesendodermal (ME) or neuroectoderm (NE) fate, the first decision during hESC differentiation. Coupled with G1 lengthening a divergent ciliation pattern emerged within the first 24 hours of induced lineage specification and these changes heralded a neuroectoderm decision before any neural precursor markers were expressed. By day 2, increased ciliation in NE precursors induced autophagy that resulted in the inactivation of Nrf2. Nrf2 binds directly to upstream regions of the OCT4 and NANOG genes to promote their expression and represses NE derivation. Nrf2 suppression was sufficient to rescue poorly neurogenic iPSC lines. Only after these events have been initiated do neural precursor markers get expressed at day 4. Thus we have identified a primary cilium-autophagy-Nrf2 (PAN) axis coupled to cell cycle progression that directs hESCs toward NE. Transcriptome analysis of hESC-derived neuroectoderm and mesendoderm cells

ORGANISM(S): Homo sapiens

SUBMITTER: Kenneth Kosik

PROVIDER: E-GEOD-69982 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Primary cilium-autophagy-Nrf2 (PAN) axis links the cell cycle to neuroectoderm fate in human embryonic stem cells

Project description:Under defined differentiation conditions human embryonic stem cells (hESCs) can be directed toward a mesendodermal (ME) or neuroectoderm (NE) fate, the first decision during hESC differentiation. Coupled with G1 lengthening a divergent ciliation pattern emerged within the first 24 hours of induced lineage specification and these changes heralded a neuroectoderm decision before any neural precursor markers were expressed. By day 2, increased ciliation in NE precursors induced autophagy that resulted in the inactivation of Nrf2. Nrf2 binds directly to upstream regions of the OCT4 and NANOG genes to promote their expression and represses NE derivation. Nrf2 suppression was sufficient to rescue poorly neurogenic iPSC lines. Only after these events have been initiated do neural precursor markers get expressed at day 4. Thus we have identified a primary cilium-autophagy-Nrf2 (PAN) axis coupled to cell cycle progression that directs hESCs toward NE.

2016-03-24 | GSE69982 | GEO

Co-immumnoprecipitation experiments to identify protein bindining partners of CSDE1

Project description:While the transcriptional network of human embryonic stem cells (hESCs) has been extensively studied, relatively little is known about how post-transcriptional modulations determine hESC function. RNA-binding proteins play central roles in RNA regulation, including translation and turnover. Here we show that the RNA-binding protein CSDE1 is highly expressed in hESCs to maintain their undifferentiated state and prevent default neural fate. Notably, loss of CSDE1 accelerates neural differentiation and potentiates neurogenesis. Conversely, ectopic expression of CSDE1 impairs neural differentiation. We find that CSDE1 post-transcriptionally modulates core components of multiple regulatory nodes of hESC identity, neuroectoderm commitment and neurogenesis. Among these key pro-neural/neuronal factors, CSDE1 binds fatty acid binding protein 7 (FABP7) and vimentin (VIM) mRNAs as well as transcripts involved in neuron projection development regulating their stability and translation. Thus, our results uncover CSDE1 as a central post-transcriptional regulator of hESC identity and neurogenesis. This proteomics dataset contains the data from co-immunopreciptation experiments using CSDE1 antibody in hESCs

2018-05-16 | PXD007271 | Pride

A post-transcriptional program coordinated by CSDE1 prevents intrinsic neural differentiation of human embryonic stem cells

Project description:We compared hESCs with their neuronal counterpart to quantify differences in the expression of cold-shock domain containing proteins. While the transcriptional network of human embryonic stem cells (hESCs) has been extensively studied, relatively little is known about how post-transcriptional modulations determine hESC function. RNA-binding proteins play central roles in RNA regulation, including translation and turnover. Here we show that the RNA-binding protein CSDE1 is highly expressed in hESCs to maintain their undifferentiated state and prevent default neural fate. Notably, loss of CSDE1 accelerates neural differentiation and potentiates neurogenesis. Conversely, ectopic expression of CSDE1 impairs neural differentiation. We find that CSDE1 post-transcriptionally modulates core components of multiple regulatory nodes of hESC identity, neuroectoderm commitment and neurogenesis. Among these key pro-neural/neuronal factors, CSDE1 binds fatty acid binding protein 7 (FABP7) and vimentin (VIM) mRNAs as well as transcripts involved in neuron projection development regulating their stability and translation. Thus, our results uncover CSDE1 as a central post-transcriptional regulator of hESC identity and neurogenesis.

2018-05-16 | PXD007738 | Pride

A post-transcriptional program coordinated by CSDE1 prevents intrinsic neural differentiation of human embryonic stem cells

2018-05-16 | PXD007270 | Pride

Genome-wide profile of 5-hydroxymethylcytosine (5-hmC) in H9 human embryonic stem cells (hESCs)

Project description:The link between single cell variation and population level fate choices lacks an explanation despite extensive observations of gene expression and epigenetic variation among individual cells. Here, we found that single human embryonic stem cells (hESCs) have different and biased differentiation potentials toward either neuroectoderm or mesendoderm depending on their G1 lengths before the onset of differentiation. Single cell variation in G1 length establishes a probability distribution in which increased variation biases stem cells toward neuroectoderm. Although sister stem cells generally share G1 lengths, a variable proportion of cells have asymmetric G1 lengths, which maintains the population dispersion. WNT levels control the G1 length distribution apparently as a means of priming the fate of hESC populations once they undergo differentiation. Global 5-hydroxymethylcytosine levels are regulated by G1 length and thereby link G1 length to differentiation outcomes of hESCs. Our findings suggest G1 length distribution links intra-population heterogeneity to population outcome.

2019-01-01 | GSE113236 | GEO

NANOG-OCT4-SOX2 Regulatory Module in Human Embryonic Stem Cells (dataset 3)

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

Eomes and Brachyury control pluripotency exit and germ-layer segregation by changing the chromatin state

Project description:We aimed to elucidate molecular mechanisms of first lineage decision in the mouse pluripotent epiblast that segregates mesoderm and endoderm (ME) from neuroectoderm (NE). By analyzing mouse embryonic stem cells (ESCs) and embryos deficient for two T-box (Tbx) transcription factors Eomes and Brachyury we demonstrate that this process is controlled by the changes in the chromatin accessibility of ME gene enhancers and activation of the target genes, but also direct repression the opposing pluripotency and NE gene programs.

2019-12-02 | GSE128466 | GEO

Discovery of consensus gene signature and intermodular connectivity defining self-renewal of human embryonic stem cells

Project description:Comparison of gene expression signatures in undifferentiated hESCs against differentiated embryoid bodies to identify key signatures defining self-renewal of hESCs. Using H1 and H9 hESC lines, we performed gene expression microarray analysis (Affymetrix Human Genome U133 Plus 2.0 Array) and analyzed the interaction patterns of 54,614 genes using WGCNA in R programming

2014-01-18 | E-GEOD-54186 | biostudies-arrayexpress

Genome Wide Profiling of p53 Response to Differentiation or DNA Damage of Human Embryonic Stem Cells

Project description:Tumor suppressor p53 promotes differentiation of human embryonic stem cells (hESCs), but an in-depth understanding of mechanism is lacking. Here, we define p53 functions in hESCs by genome wide profiling of p53 chromatin interactions and intersection with gene expression during early differentiation and in response to DNA damage. During differentiation, p53 targets and regulates a unique collection of genes, many of which encode transcription factors and developmental regulators with chromatin structure poised by OCT4 and NANOG and marked by repressive H3K27me3 in pluripotent hESCs. In contrast, genes associated with cell migration and motility are bound by p53 specifically after DNA damage. Surveillance functions of p53 in regulation of cell death and cell cycle genes are conserved during both DNA damage and differentiation. Our findings expand the registry of p53 -regulated genes in hESCs and define specific functions of p53 in opposing pluripotency, which are highly distinct from stress-induced p53 response in stem cells. Identification of p53 binding sites in hESC under three conditions: Pluripotent, DNA damaged, Differentiating

2013-10-18 | E-GEOD-39762 | biostudies-arrayexpress

NANOG-OCT4-SOX2 Regulatory Module in Human Embryonic Stem Cells (dataset 4)

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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