Similar Datasets
Project description:Using the Notch signaling pathway, hematopoietic stem and progenitor cells (HSPC) sense and respond to the surrounding microenvironment to regulate cell fate outcome. Our previous studies have indicated that quantitative differences in Notch signal strength mediate cell-fate decisions during hematopoiesis. Low signal strength favors HSPC self-renewal, along with inhibition of myelopoiesis, whereas high signal strength promotes T cell differentiation. The basis for target gene selectivity in response to quantitative differences in Notch signal strength is unknown. Focusing on the high dose dependent induction of the T cell lineage, we found that targets essential for T cell commitment, including IL2ra, CD3 and Rag1, establish promoter DNA accessibility only upon exposure to high levels of Notch signaling. We further find that low promoter CpG content is a feature capable of maintaining the ground state DNA inaccessibility of these lineage determining genes. Our results suggest that DNA inaccessibility at the promoters of essential T cell commitment genes, mediated in part through low CpG content, provides robust protection against stochastic activation in inappropriate Notch signaling contexts, ensuring the maintenance of HSPC developmental plasticity.
2021-03-25 | GSE142736 | GEO
Project description:Using the Notch signaling pathway, hematopoietic stem and progenitor cells (HSPC) sense and respond to the surrounding microenvironment to regulate cell fate outcome. Our previous studies have indicated that quantitative differences in Notch signal strength mediate cell-fate decisions during hematopoiesis. Low signal strength favors HSPC self-renewal, along with inhibition of myelopoiesis, whereas high signal strength promotes T cell differentiation. The basis for target gene selectivity in response to quantitative differences in Notch signal strength is unknown. Focusing on the high dose dependent induction of the T cell lineage, we found that targets essential for T cell commitment, including IL2ra, CD3 and Rag1, establish promoter DNA accessibility only upon exposure to high levels of Notch signaling. We further find that low promoter CpG content is a feature capable of maintaining the ground state DNA inaccessibility of these lineage determining genes. Our results suggest that DNA inaccessibility at the promoters of essential T cell commitment genes, mediated in part through low CpG content, provides robust protection against stochastic activation in inappropriate Notch signaling contexts, ensuring the maintenance of HSPC developmental plasticity.
2021-03-25 | GSE142738 | GEO
Project description:DNA accessibility determines the level of Notch signal strength necessary for lineage specific target gene expression
| PRJNA598166 | ENA
Project description:DNA accessibility determines the level of Notch signal strength necessary for lineage specific target gene expression (RNA-Seq)
| PRJNA598171 | ENA
Project description:DNA accessibility determines the level of Notch signal strength necessary for lineage specific target gene expression (Dnase-Seq)
| PRJNA598169 | ENA
Project description:Acquisition of the arterial and haemogenic endothelium fates concurrently occur in the aorta-gonad-mesonephros (AGM) region prior to haematopoietic stem cell (HSC) generation. The arterial programme depends on Dll4 and the haemogenic endothelium/HSC on Jag1-mediated Notch1 signalling. How Notch1 distinguishes and executes these different programmes in response to particular ligands is poorly understood. By using two Notch1 activation trap mouse models with different sensitivity, here we show that arterial endothelial cells and HSCs originate from distinct precursors, characterized by different Notch1 signal strengths. Microarray analysis on AGM subpopulations demonstrates that the Jag1 ligand stimulates low Notch strength, inhibits the endothelial programme and is permissive for HSC specification. In the absence of Jag1, endothelial cells experience high Dll4-induced Notch activity and select the endothelial programme, thus precluding HSC formation. Interference with the Dll4 signal by ligand-specific blocking antibodies is sufficient to inhibit the endothelial programme and favour specification of the haematopoietic lineage.
| S-EPMC4634136 | biostudies-literature
Project description:Being a transcription factor, Shox2 binds to specific DNA sites to regulate gene expression via modulating chromatin status. To investigate the impact of Shox2 on the chromatin accessible landscape in the anterior hard palate, we subjected FACS-sorted Shox2+ cells from the palate of E14.5 Shox2Cre/+;Nkx2.5F/F;R26RmTmG and Shox2Cre/-;Nkx2.5F/F;R26RmTmG mice to ATAC-Seq analysis.
2019-10-23 | GSE129538 | GEO
Project description:The strength of Notch signaling contributes to pleiotropic actions of Notch; however, we do not yet have a full understanding of the molecular regulation of Notch-signaling strength. We have investigated the mode of Notch activation in binary fate specification in the Drosophila spermathecal linage, where Notch is asymmetrically activated across three divisions to specify different cell fates. Using clonal analysis, we show that Delta (Dl) serves as the ligand for Notch in the first and second divisions. Dl and Serrate (Ser) function redundantly in the third division. Compared with the third division, cell-fate decision in the second division requires a lower level of Suppressor of Hairless protein, and, consequently, a lower level of Notch signaling. Several Notch endosomal trafficking regulators differentially regulate Notch signaling between the second and third divisions. Here, we demonstrate that cell differentiation in spermathecae involves different Notch-activation modes, Notch-signaling strengths and Notch-trafficking regulations. Thus, the Drosophila spermathecal lineage is an exciting model for probing the molecular mechanisms that modulate the Notch signaling pathway.
| S-EPMC7033723 | biostudies-literature
Project description:Thymic precursors expressing the pre-T cell receptor (TCR), the gammadeltaTCR, or the alphabetaTCR can all enter the CD4+ 8+ alphabeta lineage, albeit with different efficacy. Here it is shown that proliferation and differentiation of precursors with the different TCRs into alphabeta lineage cells require Notch signaling at the DN3 stage of thymic development. At the DN4 stage, Notch signaling still significantly contributes to the generation of alphabeta T cells. In particular, in alphabeta lineage commitment, the pre-TCR synergizes more efficiently with Notch signals than the other two TCRs, whereas gammadeltaTCR-expressing cells can survive and expand in the absence of Notch signals, even though Notch signaling enhances their proliferation. These observations suggest a new model of alphabeta versus gammadelta lineage choice in which lineage fate is determined by the extent of synergy between TCR and Notch signaling and in which the evolutionarily recent advent of the cell-autonomously signaling pre-TCR increased the efficacy of alphabeta T cell generation.
| S-EPMC2118312 | biostudies-literature
Project description:The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway is a cytosolic sensor of microbial and host-derived DNA and plays a key role in innate immunity. Activation of STING by cyclic dinucleotide (CDN) ligands in human monocytes induces a type I interferon response and production of pro-inflammatory cytokines associated with the induction of massive cell death. In this study we have re-evaluated the effect of signal strength of STING activation on the cytokine plasticity of human monocytes. CDN (2'3'c-GAMP) and non-CDN (diABZI, MSA-2) STING ligands in the range of EC50 concentrations (15 μM 2'3'c-GAMP, 100 nM diABZI, 25 μM MSA-2) induced IFN-β, IP-10, and large amounts of IL-1β and TNF-α, but no IL-10 or IL-19. Interestingly, LPS-induced production of IL-10 and IL-19 was abolished in the presence of diABZI or MSA-2, whereas IL-1β and TNF-α were not inhibited. Surprisingly, we observed that tenfold lower (MSA-2, i.e. 2.5 μM) or 100-fold lower (diABZI, i.e. 1 nM) concentrations strongly stimulated secretion of anti-inflammatory IL-10 and IL-19, but little of IL-1β and TNF-α. Induction of IL-10 was associated with up-regulation of PRDM1 (Blimp-1). While cytokine secretion stimulated by the higher concentrations was accompanied by apoptosis as shown by cleavage of caspase-3 and PARP-1, the low concentrations did not trigger overt cell death yet induced cleavage of gasdermin-D. Our results reveal a previously unrecognized plasticity of human monocytes in their signal strength-dependent production of pro- versus anti-inflammatory cytokines upon STING activation.
| S-EPMC9590392 | biostudies-literature