PRC2/Eed Downregulates Hedgehog Signaling through Activation of Gli3 Expression in Cortical Neurogenesis
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ABSTRACT:
PROVIDER: PRJNA717267 | ENA |
REPOSITORIES: ENA
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Project description:This SuperSeries is composed of the SubSeries listed below.
2022-09-21 | GSE169653 | GEO
Project description:Purpose: The response to Hedgehog signaling in the limb is driven by GLI bound enhancers and the majority of Hh targets in the developing limb bud are regulated solely by the activity of GLI-repressor. Currently we do not have a comprehensive understanding of how GLI bound enhancers respond Hedgehog signaling. The goal of this study is to identify how GLI bound enhancers are regulated by Hedgehog signaling and specifically by GLI-repressor. Methods: ChIP-seq was performed in Embryonic day 10.5 mouse limb buds from mice with endogenously FLAG tagged Gli3. Results: We identified 7282 GLI3 binding regions in the E10.5 limb bud.
2020-01-21 | GSE133710 | GEO
Project description:Before birth B-cells develop in the fetal liver (FL). Here we show that Gli3 activity in the FL stroma is required for B-cell development. In the Gli3-deficient FL B-cell development was reduced at multiple stages, whereas the Sonic hedgehog (Shh)-deficient FL showed increased B-cell development, and Gli3 functioned to repress Shh transcription. Use of a transgenic Hedgehog (Hh)-reporter mouse showed that Shh signals directly to developing B-cells, and that Hh pathway activation was increased in developing B-cells from Gli3-deficient fetal liver. RNAsequencing confirmed that Hh-mediated transcription is increased in B-lineage cells from Gli3-deficient FL, and showed that these cells expressed reduced levels of B-lineage transcription factors and BCR/pre-BCR-signalling genes. We showed that expression of the master regulators of B-cell development, Ebf1 and Pax5, is reduced in developing B-cells from Gli3-deficient FL and increased in Shh-deficient FL, and that in vitro Shh-treatment or neutralisation can repress or induce their expression respectively.
2017-05-09 | GSE81467 | GEO
Project description:The histone methyltransferase complex PRC2 is a crucial chromatin modifier and controls key steps in developmental transitions and cell fate choices. Mutations in PRC2 core subunits are found in Weaver syndrome with craniofacial defects, intellectual disabilities, and often macrocephaly, but its pathogenicity and molecular mechanism are unknown. Here, we examined the role of PRC2/Eed in neural stem/progenitor cells (NSPCs) during cortical neurogenesis We found that Eed is highly expressed in embryonic cerebral cortex and specific deletion of Eed in forebrain reduced the number of upper layer neurons but not deeper layer neurons and ultimately contributed to abnormal cortical development. In addition, our results revealed that PRC2/Eed regulated Hedgehog signaling pathway through activation of Gli3 not dependent on H3K27me3 but H3K27ac. What?s more, Increased Gli3 in NSPCs could reduce Gli1 expression and contribute to the defects of cortical neurogenesis caused by Eed deletion. Finally, Hedgehog signaling activation with small molecule SAG or genetic inactivation of Ptch1 could partially rescue the cortical neurogenesis defects in vivo after Eed depletion. In general, we identified a novel PRC2/Eed-Gli3-Gli1 regulatory axis that is critical for normal cortical neurogenesis. Our findings define a critical function for PRC2/Eed in cortical development and shed light on the genetic basis of intellectual disabilities of neural developmental disorders caused by PRC2/Eed mutation.
2022-09-21 | GSE169401 | GEO
Project description:The histone methyltransferase complex PRC2 is a crucial chromatin modifier and controls key steps in developmental transitions and cell fate choices. Mutations in PRC2 core subunits are found in Weaver syndrome with craniofacial defects, intellectual disabilities, and often macrocephaly, but its pathogenicity and molecular mechanism are unknown. Here, we examined the role of PRC2/Eed in neural stem/progenitor cells (NSPCs) during cortical neurogenesis We found that Eed is highly expressed in embryonic cerebral cortex and specific deletion of Eed in forebrain reduced the number of upper layer neurons but not deeper layer neurons and ultimately contributed to abnormal cortical development. In addition, our results revealed that PRC2/Eed regulated Hedgehog signaling pathway through activation of Gli3 not dependent on H3K27me3 but H3K27ac. What?s more, Increased Gli3 in NSPCs could reduce Gli1 expression and contribute to the defects of cortical neurogenesis caused by Eed deletion. Finally, Hedgehog signaling activation with small molecule SAG or genetic inactivation of Ptch1 could partially rescue the cortical neurogenesis defects in vivo after Eed depletion. In general, we identified a novel PRC2/Eed-Gli3-Gli1 regulatory axis that is critical for normal cortical neurogenesis. Our findings define a critical function for PRC2/Eed in cortical development and shed light on the genetic basis of intellectual disabilities of neural developmental disorders caused by PRC2/Eed mutation.
2022-09-21 | GSE169395 | GEO
Project description:Mutations in the embryonic ectoderm development (EED) cause Weaver syndrome, but whether and how EED affects embryonic brain development remains elusive. Here, we generated a mouse model in which Eed was deleted in the forebrain to investigate the role of EED. We found that deletion of Eed decreased the number of upper-layer neurons but not deeper-layer neurons starting at E16.5. Transcriptomic and genomic occupancy analyses revealed that the epigenetic states of a group of cortical neurogenesis-related genes were altered in Eed knockout forebrains, followed by a decrease of H3K27me3 and an increase of H3K27ac marks within the promoter regions. The switching of H3K27me3 to H3K27ac modification promoted the recruitment of RNA-Pol2, thereby enhancing its expression level. The small molecule activator SAG or Ptch1 knockout for activating Hedgehog signaling can partially rescue aberrant cortical neurogenesis. Taken together, we proposed a novel EED-Gli3-Gli1 regulatory axis that is critical for embryonic brain development.
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Project description:Satellite stem cells are required for the growth, maintenance, and regeneration of skeletal muscle. Quiescent satellite stem cells possess a primary cilium, a structure that regulates the processing of the GLI-family of transcription factors. We find that GLI3, specifically, plays a critical role in satellite cell activation. Strikingly, primary cilia-mediated processing of GLI3, independent of canonical Hedgehog signaling, is required to maintain satellite cells in a G0 dormant state, as satellite cells lacking GLI3 enter GAlert in absence of injury. Furthermore, GLI3 depletion or inhibition of its processing stimulates symmetrical division in satellite cells and expansion of the stem cell pool. As a result, satellite cells lacking GLI3 display rapid cell-cycle entry, increased proliferation and augmented self-renewal, and markedly enhanced long-term regenerative capacity. Therefore, our results reveal an essential role for primary cilia processing of GLI3 in regulating muscle stem cell activation.
2022-03-30 | GSE144871 | GEO
Project description:Sonic hedgehog (Shh) signals via Gli transcription factors to direct digit number and identity in the vertebrate limb. We have characterized the Gli-dependent cis-regulatory network through a combination of whole genome ChIP-on-chip and transcriptional profiling of the developing mouse limb. These analyses identified approximately 5,000 high quality Gli3 binding sites, including all known Gli-dependent enhancers. Discrete binding regions exhibit a higher-order clustering, highlighting the complexity of cis-regulatory interactions. Further, Gli3 binds inertly to previously identified neural-specific Gli enhancers, demonstrating the accessibility of their cis-regulatory elements. Intersection of DNA binding data with gene expression profiles predicted 205 putative limb target genes. The supplementary bed file contains all 5,274 high quality binding Gli3 binding sites reported in the paper.
2008-09-15 | GSE11062 | GEO
Project description:Epigenetic modification by polycomb repressive complex (PRC) molecules appears to have a role in tumorigenesis and aggressiveness of neuroblastoma (NB). Embryonic Ectoderm Development (EED) is a member of PRC2 complex and binds the H3K27me3 mark deposited by EZH2, via propagation on adjacent nucleosomes. Here we studied the molecular roles of EED in MYCN-amplified neuroblastoma cells by using EED-knocked down shRNAs, EED-knocked out sgRNAs, and EED small molecule inhibitor EED226. EED suppression profoundly inhibited the NB cell proliferation and flat-and soft agar colony formation. Transcriptome analysis by microarray of the EED-KD NB cells indicated the de-repression of the cell cycle regulated and differentiation-related genes; GSEA analysis results suggested that cell cycle repressed gene sets were strongly upregulated. Further, epigenetic treatment by the combination of EED inhibitor EED226 and HDAC inhibitor valproic acid effectively suppressed NB cell proliferation and colony formation. The combinatory epigenetic treatment up-regulated the cell cycle regulation- and differentiation-related genes.
2022-09-03 | GSE183369 | GEO