scholarly journals Coordination of EZH2 and SOX2 specifies human neural fate decision

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuan Zhao ◽  
Tianyu Wang ◽  
Yanqi Zhang ◽  
Liang Shi ◽  
Cong Zhang ◽  
...  
Keyword(s):  
Neural Progenitor Cells ◽  
Embryonic Stem ◽  
Neural Induction ◽  
Aberrant Expression ◽  
Knock Out ◽  
Neural Fate ◽  
Neural Genes ◽  
Human Neural Progenitor Cells ◽  
Fate Decision ◽  
Polycomb Repressive Complexes

AbstractPolycomb repressive complexes (PRCs) are essential in mouse gastrulation and specify neural ectoderm in human embryonic stem cells (hESCs), but the underlying molecular basis remains unclear. Here in this study, by employing an array of different approaches, such as gene knock-out, RNA-seq, ChIP-seq, et al., we uncover that EZH2, an important PRC factor, specifies the normal neural fate decision through repressing the competing meso/endoderm program. EZH2−/− hESCs show an aberrant re-activation of meso/endoderm genes during neural induction. At the molecular level, EZH2 represses meso/endoderm genes while SOX2 activates the neural genes to coordinately specify the normal neural fate. Moreover, EZH2 also supports the proliferation of human neural progenitor cells (NPCs) through repressing the aberrant expression of meso/endoderm program during culture. Together, our findings uncover the coordination of epigenetic regulators such as EZH2 and lineage factors like SOX2 in normal neural fate decision.

scholarly journals The transcription factor Pou3f1 promotes neural fate commitment via activation of neural lineage genes and inhibition of external signaling pathways

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Qingqing Zhu ◽  
Lu Song ◽  
Guangdun Peng ◽  
Na Sun ◽  
Jun Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Neural Progenitor Cells ◽  
Embryonic Stem ◽  
Neural Induction ◽  
Induction Programs ◽  
Neural Lineage ◽  
Neural Fate ◽  
Epiblast Stem Cells ◽  
Genome Wide

The neural fate commitment of pluripotent stem cells requires the repression of extrinsic inhibitory signals and the activation of intrinsic positive transcription factors. However, how these two events are integrated to ensure appropriate neural conversion remains unclear. In this study, we showed that Pou3f1 is essential for the neural differentiation of mouse embryonic stem cells (ESCs), specifically during the transition from epiblast stem cells (EpiSCs) to neural progenitor cells (NPCs). Chimeric analysis showed that Pou3f1 knockdown leads to a markedly decreased incorporation of ESCs in the neuroectoderm. By contrast, Pou3f1-overexpressing ESC derivatives preferentially contribute to the neuroectoderm. Genome-wide ChIP-seq and RNA-seq analyses indicated that Pou3f1 is an upstream activator of neural lineage genes, and also is a repressor of BMP and Wnt signaling. Our results established that Pou3f1 promotes the neural fate commitment of pluripotent stem cells through a dual role, activating internal neural induction programs and antagonizing extrinsic neural inhibitory signals.

scholarly journals Neural Induction, Neural Fate Stabilization, and Neural Stem Cells

2002 ◽  
Vol 2 ◽  
pp. 1147-1166 ◽  
Author(s):  
Sally A. Moody ◽  
Hyun-Soo Je
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Neural Stem Cells ◽  
Neural Development ◽  
Current Knowledge ◽  
Embryonic Stem ◽  
Neural Induction ◽  
Neural Plate ◽  
Natural Rate ◽  
Neural Fate

The promise of stem cell therapy is expected to greatly benefit the treatment of neurodegenerative diseases. An underlying biological reason for the progressive functional losses associated with these diseases is the extremely low natural rate of self-repair in the nervous system. Although the mature CNS harbors a limited number of self-renewing stem cells, these make a significant contribution to only a few areas of brain. Therefore, it is particularly important to understand how to manipulate embryonic stem cells and adult neural stem cells so their descendants can repopulate and functionally repair damaged brain regions. A large knowledge base has been gathered about the normal processes of neural development. The time has come for this information to be applied to the problems of obtaining sufficient, neurally committed stem cells for clinical use. In this article we review the process of neural induction, by which the embryonic ectodermal cells are directed to form the neural plate, and the process of neural�fate stabilization, by which neural plate cells expand in number and consolidate their neural fate. We will present the current knowledge of the transcription factors and signaling molecules that are known to be involved in these processes. We will discuss how these factors may be relevant to manipulating embryonic stem cells to express a neural fate and to produce large numbers of neurally committed, yet undifferentiated, stem cells for transplantation therapies.

scholarly journals Transcriptional profiling of MEF2-regulated genes in human neural progenitor cells derived from embryonic stem cells

Genomics Data ◽  
2015 ◽  
Vol 3 ◽  
pp. 24-27 ◽  
Author(s):  
Shing Fai Chan ◽  
Xiayu Huang ◽  
Scott R. McKercher ◽  
Rameez Zaidi ◽  
Shu-ichi Okamoto ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Progenitor Cells ◽  
Neural Progenitor Cells ◽  
Transcriptional Profiling ◽  
Embryonic Stem ◽  
Neural Progenitor ◽  
Human Neural Progenitor Cells

scholarly journals Embryonic stem cell–derived hemangioblasts remain epigenetically plastic and require PRC1 to prevent neural gene expression

Blood ◽  
2011 ◽  
Vol 117 (1) ◽  
pp. 83-87 ◽  
Author(s):  
Luca Mazzarella ◽  
Helle F. Jørgensen ◽  
Jorge Soza-Ried ◽  
Anna V. Terry ◽  
Stella Pearson ◽  
...  
Keyword(s):  
Es Cells ◽  
Embryonic Stem ◽  
Promoter Regions ◽  
Conditional Deletion ◽  
Neural Genes ◽  
Multiple Differentiation ◽  
Regulator Genes ◽  
Polycomb Repressive Complexes ◽  
Inappropriate Expression ◽  
Productive Elongation

Abstract Many lineage-specific developmental regulator genes are transcriptionally primed in embryonic stem (ES) cells; RNA PolII is bound at their promoters but is prevented from productive elongation by the activity of polycomb repressive complexes (PRC) 1 and 2. This epigenetically poised state is thought to enable ES cells to rapidly execute multiple differentiation programs and is recognized by a simultaneous enrichment for trimethylation of lysine 4 and trimethylation of lysine 27 of histone H3 (bivalent chromatin) across promoter regions. Here we show that the chromatin profile of this important cohort of genes is progressively modified as ES cells differentiate toward blood-forming precursors. Surprisingly however, neural specifying genes, such as Nkx2-2, Nkx2-9, and Sox1, remain bivalent and primed even in committed hemangioblasts, as conditional deletion of PRC1 results in overt and inappropriate expression of neural genes in hemangioblasts. These data reinforce the importance of PRC1 for normal hematopoietic differentiation and reveal an unexpected epigenetic plasticity of mesoderm-committed hemangioblasts.

scholarly journals Variant PCGF1-PRC1 links PRC2 recruitment with differentiation-associated transcriptional inactivation at target genes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hiroki Sugishita ◽  
Takashi Kondo ◽  
Shinsuke Ito ◽  
Manabu Nakayama ◽  
Nayuta Yakushiji-Kaminatsui ◽  
...  
Keyword(s):  
Stem Cells ◽  
Crucial Role ◽  
Target Genes ◽  
Embryonic Stem ◽  
Embryoid Bodies ◽  
Polycomb Group ◽  
Gene Repression ◽  
Down Regulation ◽  
Aberrant Expression ◽  
Polycomb Repressive Complexes

AbstractPolycomb repressive complexes-1 and -2 (PRC1 and 2) silence developmental genes in a spatiotemporal manner during embryogenesis. How Polycomb group (PcG) proteins orchestrate down-regulation of target genes upon differentiation, however, remains elusive. Here, by differentiating embryonic stem cells into embryoid bodies, we reveal a crucial role for the PCGF1-containing variant PRC1 complex (PCGF1-PRC1) to mediate differentiation-associated down-regulation of a group of genes. Upon differentiation cues, transcription is down-regulated at these genes, in association with PCGF1-PRC1-mediated deposition of histone H2AK119 mono-ubiquitination (H2AK119ub1) and PRC2 recruitment. In the absence of PCGF1-PRC1, both H2AK119ub1 deposition and PRC2 recruitment are disrupted, leading to aberrant expression of target genes. PCGF1-PRC1 is, therefore, required for initiation and consolidation of PcG-mediated gene repression during differentiation.

Human neural progenitor cells derived from embryonic stem cells in feeder-free cultures

2008 ◽  
Vol 76 (5) ◽  
pp. 454-464 ◽  
Author(s):  
Sujoy K. Dhara ◽  
Kowser Hasneen ◽  
David W. Machacek ◽  
Nolan L. Boyd ◽  
Raj R. Rao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Progenitor Cells ◽  
Neural Progenitor Cells ◽  
Embryonic Stem ◽  
Neural Progenitor ◽  
Human Neural Progenitor Cells

scholarly journals ADNP promotes neural differentiation by modulating Wnt/β-catenin signaling

2019 ◽  
Author(s):  
Xiaoyun Sun ◽  
Xixia Peng ◽  
Yuqing Cao ◽  
Yan Zhou ◽  
Yuhua Sun
Keyword(s):  
Wnt Signaling ◽  
Neural Development ◽  
Neural Differentiation ◽  
Developmental Disorders ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Neural Induction ◽  
Neuron Death ◽  
Aberrant Expression ◽  
Protein Levels

AbstractADNP (Activity Dependent Neuroprotective Protein) is proposed as a neuroprotective protein whose aberrant expression has been frequently linked to neural developmental disorders, including the Helsmoortel-Van der Aa syndrome. However, its role in neural development and pathology remains unclear. Using mESC (mouse embryonic stem cell) directional neural differentiation as a model, we show that ADNP is required for ESC neural induction and neuronal differentiation by maintaining Wnt signaling. Mechanistically, ADNP functions to maintain the proper protein levels of β-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC. Loss of ADNP promotes the formation of the degradation complex and hyperphosphorylation of β-Catenin by GSK3β and subsequent degradation via ubiquitin-proteasome pathway, resulting in down-regulation of key neuroectoderm developmental genes. We further show that ADNP plays key role in cerebellar neuron formation. Finally, adnp gene disruption in zebrafish embryos recapitulates key features of the mouse phenotype, including the reduced Wnt signaling, defective embryonic cerebral neuron formation and the massive neuron death. Thus, our work provides important insights into the role of ADNP in neural development and the pathology of the Helsmoortel-Van der Aa syndrome caused by ADNP gene mutation.

scholarly journals Establishment of Human Neural Progenitor Cells from Human Induced Pluripotent Stem Cells with Diverse Tissue Origins

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Hayato Fukusumi ◽  
Tomoko Shofuda ◽  
Yohei Bamba ◽  
Atsuyo Yamamoto ◽  
Daisuke Kanematsu ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Neural Progenitor Cells ◽  
Mononuclear Cells ◽  
Embryoid Body ◽  
Neural Induction ◽  
Neural Progenitor ◽  
Dermal Fibroblasts ◽  
Peripheral Blood Mononuclear ◽  
Human Neural Progenitor Cells ◽  
Induced Pluripotent

Human neural progenitor cells (hNPCs) have previously been generated from limited numbers of human induced pluripotent stem cell (hiPSC) clones. Here, 21 hiPSC clones derived from human dermal fibroblasts, cord blood cells, and peripheral blood mononuclear cells were differentiated using two neural induction methods, an embryoid body (EB) formation-based method and an EB formation method using dual SMAD inhibitors (dSMADi). Our results showed that expandable hNPCs could be generated from hiPSC clones with diverse somatic tissue origins. The established hNPCs exhibited a mid/hindbrain-type neural identity and uniform expression of neural progenitor genes.

scholarly journals ERK1/2 signalling dynamics promote neural differentiation by regulating the polycomb repressive complex

2019 ◽  
Author(s):  
Claudia I. Semprich ◽  
Vicki Metzis ◽  
Harshil Patel ◽  
James Briscoe ◽  
Kate G. Storey
Keyword(s):  
Embryonic Stem ◽  
Chromatin Accessibility ◽  
Polycomb Repressive Complex ◽  
Neural Genes ◽  
Polycomb Protein ◽  
Repressive Histone Mark ◽  
Protein Dissociation ◽  
Subsequent Loss ◽  
Fgf Signalling ◽  
Polycomb Repressive Complexes

AbstractFibroblast Growth Factor (FGF) is a neural inducer in many vertebrate embryos, but how it regulates chromatin organization to coordinate the activation of neural genes is unclear. Moreover, for differentiation to progress FGF signalling has to decline. Why this signalling dynamic is required has not been determined. Here we show that dephosphorylation of the FGF effector kinase ERK1/2 rapidly increases chromatin accessibility at neural genes in mouse embryos and, using ATAC-seq in human embryonic stem cell derived spinal cord precursors, we demonstrate that this occurs across hundreds of neural genes. Importantly, while Erk1/2 inhibition induces precocious neural gene transcription, this step involves dissociation of the polycomb repressive complex from gene loci and takes places independently of subsequent loss of the repressive histone mark H3K27me3 and transcriptional onset. We find that loss of ERK1/2 activity but not its occupancy at neural genes is critical for this mechanism. Moreover, transient ERK1/2 inhibition is sufficient for polycomb protein dissociation and this is not reversed on resumption of ERK1/2 signalling. These data indicate that ERK1/2 signalling maintains polycomb repressive complexes at neural genes, that its decline coordinates their increased accessibility and that this is a directional molecular mechanism, which initiates the process of neural commitment. Furthermore, as the polycomb repressive complexes repress but also ready genes for transcription, these findings suggest that ERK1/2 promotion of these complexes is a rite of passage for subsequent differentiation.

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