PCGF5 is required for neural differentiation of embryonic stem cells [ChIP-seq]
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ABSTRACT:
PROVIDER: PRJNA419920 | ENA |
REPOSITORIES: ENA
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Project description:Polycomb-group proteins are key regulators of the transcriptional programs that maintain stem cell identity and dictate lineage specification. Polycomb repressor complex 1 (PRC1) contains the E3 ligases RING1A/B, which monoubiquitinate lysine 119 at histone H2A (H2AK119ub1) to regulate gene expression. PRC1 has been sub-classified into six major complexes based on the presence of a PCGF subunit. Here, we find that Pcgf5, one of six PCGF paralogs, is an important requirement in the differentiation of mouse embryonic stem cells (mESCs) towards a neural cell fate. Although PCGF5 is not required for mESC self-renewal, its loss blocks mESC neural differentiation by activating the SMAD2/TGF-β signaling pathway. Inhibition of SMAD2/TGF-β signaling or rescue by overexpression of Pcgf5 can restore the capability of mESCs to differentiate towards a neural cell fate. PCGF5 works by stimulating RING1B-dependent H2AK119ub1 both in vitro and in vivo, leading to the suppression of TGF-β signaling genes. PCGF5 loss-of-function prevents the reduction of H2AK119ub1 and H3K27me3 around neural specific genes and keeps them repressed. Our results showed that PCGF5 might function as both a repressor for SMAD2/TGF-β signaling pathway and a facilitator for neural differentiation. Together, our findings reveal a critical context-specific function for PCGF5 in directing PRC1 to control cell fate.
2018-03-10 | GSE107377 | GEO
Project description:Polycomb-group proteins are key regulators of the transcriptional programs that maintain stem cell identity and dictate lineage specification. Polycomb repressor complex 1 (PRC1) contains the E3 ligases RING1A/B, which monoubiquitinate lysine 119 at histone H2A (H2AK119ub1) to regulate gene expression. PRC1 has been sub-classified into six major complexes based on the presence of a PCGF subunit. Here, we find that Pcgf5, one of six PCGF paralogs, is an important requirement in the differentiation of mouse embryonic stem cells (mESCs) towards a neural cell fate. Although PCGF5 is not required for mESC self-renewal, its loss blocks mESC neural differentiation by activating the SMAD2/TGF-β signaling pathway. Inhibition of SMAD2/TGF-β signaling or rescue by overexpression of Pcgf5 can restore the capability of mESCs to differentiate towards a neural cell fate. PCGF5 works by stimulating RING1B-dependent H2AK119ub1 both in vitro and in vivo, leading to the suppression of TGF-β signaling genes. PCGF5 loss-of-function prevents the reduction of H2AK119ub1 and H3K27me3 around neural specific genes and keeps them repressed. Our results showed that PCGF5 might function as both a repressor for SMAD2/TGF-β signaling pathway and a facilitator for neural differentiation. Together, our findings reveal a critical context-specific function for PCGF5 in directing PRC1 to control cell fate.
2018-03-10 | GSE95127 | GEO
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.
2018-05-16 | PXD007270 | Pride
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
Project description:UTX is a histone H3 lysine 27 demethylase required for development. However, the mechanisms underlying developmental gene regulation by UTX are unclear. Here, we discovered a molecular interaction between UTX and 53BP1 that regulates gene expression in a human neurogenesis model. Human 53BP1 contains a UTX-binding site that diverges from its mouse homolog by 41%, and our data suggest that the UTX-53BP1 interaction is conserved in primates but not rodents. ChIP-Seq revealed that the genome-wide targets of UTX and 53BP1 overlap by 84%. We used CRISPR-Cas9 to generate mutations of 53BP1 and UTX in human embryonic stem cells, and found that both 53BP1 and UTX are required to promote the expression of hundreds of neurogenic genes during neural differentiation. Further, 53BP1 is required for human neural progenitor differentiation into neurons. Our findings suggest that the UTX-53BP1 interaction controls gene expression important for neural differentiation in humans.
2019-02-15 | GSE108114 | GEO
Project description:Dynamic transcriptomes during neural differentiation of human embryonic stem cells revealed by short long, and paired-end sequencing In order to examine the fundamental mechanisms governing neural differentiation, we analyzed the transcriptome changes that occur during the differentiation of human embryonic stem cells (hESCs) into the neural lineage. Undifferentiated hESCs as well as cells at three stages of early neural differentiation, N1 (early initiation), N2 (neural progenitor), and N3 (early glial-like) were analyzed using a combination of single read, paired-end read, and long read RNA sequencing. The results revealed enormous complexity in gene transcription and splicing dynamics during neural cell differentiation. We found previously unannotated transcripts and spliced isoforms specific for each stage of differentiation. Interestingly, splicing isoform diversity is highest in undifferentiated hESCs and decreases upon differentiation, a phenomenon we call “isoform specialization.” During neural differentiation, we observed differential expression of many types of genes including those involved in key signaling pathways, and a large number of extracellular receptors exhibit stage-specific regulation. These results provide a valuable resource for studying neural differentiation and reveal insights into the mechanisms underlying in vitro neural differentiation of hESCs, such as neural fate specification, NPC identity maintenance and the transition from a predominantly neuronal state into one with increased gliogenic potential
2010-03-04 | GSE20301 | GEO
Project description:During in vitro differentiation, pluripotent stem cells undergo extensive remodeling of their gene expression profiles. While studied extensively at the transcriptome level, much less is known about protein dynamics, which might differ significantly from their mRNA counterparts. Here, we present deep proteome-wide measurements of protein levels during the differentiation of embryonic stem cells.
2017-01-10 | MSV000080461 | MassIVE
Project description:The purpose of this study was to examine global gene expression during the differentiation of human embryonic stem cells to more restricted neural progenitors. We developed an adherent differentiation protocol with completely defined media that produced 2 distinct classes of neuroepithelia based on timing, morphology and expression of known neural markers. The first stage of differentiation is undifferentiated human ES cells (hESCs). The second stage is aggregates of these hESCs after 6 days of separation from supportive mouse embryonic fibroblasts. The third stage is a primitive anterior neuroepithelia that arises after 10 days of differentiation and is marked by a columnar morphology, expression of Pax6 and anterior neural patterning genes. The fourth stage peaks at 17 days when cells form rosettes that resemble the neural tube and express the pan-neural marker Sox1.
2007-03-09 | E-SMDB-3806 | biostudies-arrayexpress
Project description:Timecourse RNA-seq of mouse embryonic stem cells during neural differentiation
| PRJEB38728 | ENA
Project description:UTX is a histone H3 lysine 27 demethylase required for development. However, the mechanisms underlying developmental gene regulation by UTX are unclear. Here, we discovered a molecular interaction between UTX and 53BP1 that regulates gene expression in a human neurogenesis model. Human 53BP1 contains a UTX-binding site that diverges from its mouse homolog by 41%, and our data suggest that the UTX-53BP1 interaction is conserved in primates but not rodents. ChIP-Seq revealed that the genome-wide targets of UTX and 53BP1 overlap by 84%. We used CRISPR-Cas9 to generate mutations of 53BP1 and UTX in human embryonic stem cells, and found that both 53BP1 and UTX are required to promote the expression of hundreds of neurogenic genes during neural differentiation. Further, 53BP1 is required for human neural progenitor differentiation into neurons. Our findings suggest that the UTX-53BP1 interaction controls gene expression important for neural differentiation in humans.
2019-02-15 | GSE108115 | GEO