WNT signaling memory is required for ACTIVIN to function as a morphogen
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ABSTRACT:
PROVIDER: PRJNA437954 | ENA |
REPOSITORIES: ENA
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Project description:It has now become clear that the process of fate specification during early embryogenesis is mediated by a handful of key signaling pathways. However, how the temporal and spatial integration of these signals plays out to give rise to self-organization of tissues remains obscure. Here we use artificial human gastruloids and quantitative single-cell analysis to dissect the temporal integration of two key pathways WNT and ACTIVIN that along with BMP control gastrulation and primitive streak patterning in model systems. We showed that ACTIVIN elicits a transient signaling response, as well as a transient induction of differentiation. However, unlike BMP and WNT, ACTIVIN cannot induce stable primitive streak formation and mesodermal patterning. Pre-exposure to WNT switches the response of cells to ACTIVIN whereby it becomes a concentration dependent morphogen. This provides evidence for WNT signaling memory that occurs at the transcriptional level and not as a modifier of ACTIVIN signaling dynamics.
2018-10-22 | GSE111717 | GEO
Project description:We report genome-wide changes in chromatin state and transcriptional output following Wnt-priming and subsequent Activin induced differentiation of human embryonic stem cell and the effects of BET bromodomain inhibition during Wnt-priming. The two signals, Wnt and Activin, although provided sequentially, result in stable mesendoderm differentiation (Yoney et al., 2018).
2021-06-06 | GSE176222 | GEO
Project description:Activin and Wnt signaling are necessary and sufficient for mesendoderm (ME) differentiation of human embryonic stem cells (hESCs). In this study, we report that during the Activin and Wnt induced ME differentiation, Activin/Smad2 induces decrease of the repressive histone modification H3K27me3 by promoting proteasome-dependent degradation of EZH2. As a result, recruitment of the forkhead protein FOXH1 on open chromatin regions integrates the signals of Activin/Smad2 and Wnt/β-catenin to activate the expression of the ME genes including HAS2 and ALDH3A2. Knockdown of HAS2 and ALDH3A2 greatly attenuates ME differentiation. These findings unveil a pathway from extracellular signals to epigenetic modification-mediated gene activation during ME commitment.
2018-09-29 | GSE113047 | GEO
Project description:Self-organization of discrete fates in human gastruloids is mediated by a hierarchy of signaling pathways. How these pathways are integrated in time, and whether cells maintain a memory of their signaling history remains obscure. Here, we dissect the temporal integration of two key pathways, WNT and ACTIVIN, which along with BMP control gastrulation. CRISPR/Cas9-engineered live reporters of SMAD1, 2 and 4 demonstrate that in contrast to the stable signaling by SMAD1, signaling and transcriptional response by SMAD2 is transient, and while necessary for pluripotency, it is insufficient for differentiation. Pre-exposure to WNT, however, endows cells with the competence to respond to graded levels of ACTIVIN, which induces differentiation without changing SMAD2 dynamics. This cellular memory of WNT signaling is necessary for ACTIVIN morphogen activity. A re-evaluation of the evidence gathered over decades in model systems, re-enforces our conclusions and points to an evolutionarily conserved mechanism.
| S-EPMC6234031 | biostudies-literature
Project description:Morphogen signalling forms an activity gradient and instructs cell identities in a signalling strength-dependent manner to pattern developing tissues. However, developing tissues also undergo dynamic morphogenesis, which may produce cells with unfit morphogen signalling and consequent noisy morphogen gradient. Here we show that a cell competition-related system corrects such noisy morphogen gradients. Zebrafish imaging analyses of the Wnt/β-catenin signalling gradient, which acts as a morphogen to establish embryonic anterior-posterior patterning, revealed that unfit cells with abnormal Wnt/β-catenin activity spontaneously appear and produce noise in the gradient. Communication between unfit and neighbouring fit cells via cadherin proteins stimulates apoptosis of the unfit cells by activating Smad signalling and reactive oxygen species production. This unfit cell elimination is required for proper Wnt/β-catenin gradient formation and consequent anterior-posterior patterning. Because this gradient controls patterning not only in the embryo but also in adult tissues, this system may support tissue robustness and disease prevention.
2019-09-15 | GSE133526 | GEO
Project description:Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing immune memory. Yet the transcription factors that regulate these processes are poorly defined, as are the target genes they control and they chromatin-modifying complexes they recruit. Using model pathogens and three different mouse models, we find that the widely expressed transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of functional CD4 memory. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4 T cells, and to generate robust Il2 expression upon restimulation. Gene expression profiling indicates that OCA-B is also required for the robust re-expression of multiple other targets including Ifng and Il17a. ChIPseq identify multiple differentially expressed direct targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2 and Ifng. The findings pinpoint Oct1 and OCA-B as unanticipated mediators of CD4 T cell memory. Examination of transcription factor occupancy in CD4 T cells upon rest and restimulation.
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Project description:Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastasis spread. Signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming grow factor (TGF)- is a recognized suppressor of NK cells that inhibits IL-15 dependent signaling events and induces cellular transdifferentiation, however the role of other SMAD signaling pathways in NK cells is unknown. We used a global, label-free proteomics approach to compare the protein expression profiles of NK cells in the presence of TGF-b or activin-A.
2020-04-06 | PXD011672 | Pride
Project description:Epigenetic changes are crucial for the generation of immunological memory1-4. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing immune memory. Yet the transcription factors that regulate these processes are poorly defined, as are the chromatin modifying complexes they recruit and the chromatin modifications they control. Using pathogen infection models and three different mouse models, including a new conditional allele, we find that the widely expressed transcription factor Oct15, and its cofactor OCA-B6,7, are selectively required the in vivo generation of functional CD4 memory. In vitro, both proteins are also required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4 T cells, and to generate robust Il2 expression upon restimulation. OCA-B is also required for the robust re-expression of other known targets including Il17a, and Ifng. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a8 to targets such as Il2 and Ifng. The findings pinpoint Oct1 and OCA-B as unanticipated mediators of CD4 T cell memory. Examination of 4 different conditions in 2 genotypes
2015-09-17 | E-GEOD-62202 | biostudies-arrayexpress
Project description:Activin A is Required for the Self-Renewal of Aortic Sox2+ Neurospheres
| PRJNA854964 | ENA
Project description:The combination of Wnt pathway activation by the GSK3 inhibitor and ERK pathway inhibition by the MEK inhibitor, which is known as 2i is a well-established method to maintain mouse embryonic stem cell (mESC) self-renewal. Here we show that Activin A also has the ability to promote naive pluripotency of mESCs when combined with the MEK inhibitor PD0325901. mESCs were efficiently propagated in a medium containing both Activin A and the MEK inhibitor (PD0325901). mESCs cultured in Activin+PD retained a pluripotency state that expresses high levels of naive pluripotency-related transcription factors and is able to differentiate into three germ layers under appropriate conditions. They also showed naive pluripotency features, including the preferential usage of the Oct4 distal enhancer and the self-renewal response to Wnt pathway activation. Our finding provides another way to maintain the naive pluripotency state and reveals a role of Activin/Nodal/TGF-β signaling in stabilizing self-renewal gene regulatory networks in mESCs. To compare the gene expression patterns of naive and primed pluripotency states and their responses to Wnt and ERK1/2 MAPK pathway, we performed genome-wide gene expression analysis of mESCs and EpiLCs, and those treated with Wnt pathway activator alone or Wnt pathway activator combined with ERK1/2 MAPK pathway inhibitior.
2018-11-02 | GSE74963 | GEO