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β-catenin regulates primitive streak induction through collaborative interactions with SMAD2/3 and OCT4

ABSTRACT: Canonical Wnt and Nodal signaling are both required for induction of the primitive streak (PS), which guides organization of the early embryo. The Wnt effector β-catenin is thought to function in these early lineage specification decisions via transcriptional activation of Nodal signaling. Here, we demonstrate a broader role for β-catenin in PS formation by analyzing its genome-wide binding in a human embryonic stem cell model of PS induction. β-catenin occupies regulatory regions in numerous PS and neural crest genes, and direct interactions between β-catenin and the Nodal effectors SMAD2/3 are required at these regions for PS gene activation. Furthermore, OCT4 binding in proximity to these sites is likewise required for PS induction, suggesting a collaborative interaction between β-catenin and OCT4. Induction of neural crest genes by β-catenin is repressed by SMAD2/3, ensuring proper lineage specification. This study provides mechanistic insight into how Wnt signaling controls early cell lineage decisions. Examination of β-catenin binding in hESC incubated in media control (RPMI), media containing CHIR or CHIR+SB for 6h and analyzed by ChIP-sequencing

ORGANISM(S): Homo sapiens

SUBMITTER: Karen Schachter

PROVIDER: E-GEOD-58476 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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β-catenin regulates primitive streak induction through collaborative interactions with SMAD2/3 and OCT4

Project description:Canonical Wnt and Nodal signaling are both required for induction of the primitive streak (PS), which guides organization of the early embryo. The Wnt effector β-catenin is thought to function in these early lineage specification decisions via transcriptional activation of Nodal signaling. Here, we demonstrate a broader role for β-catenin in PS formation by analyzing its genome-wide binding in a human embryonic stem cell model of PS induction. β-catenin occupies regulatory regions in numerous PS and neural crest genes, and direct interactions between β-catenin and the Nodal effectors SMAD2/3 are required at these regions for PS gene activation. Furthermore, OCT4 binding in proximity to these sites is likewise required for PS induction, suggesting a collaborative interaction between β-catenin and OCT4. Induction of neural crest genes by β-catenin is repressed by SMAD2/3, ensuring proper lineage specification. This study provides mechanistic insight into how Wnt signaling controls early cell lineage decisions.

2015-03-31 | GSE58476 | GEO

Enhanced Pathogenicity of Th17 cells Generated in the Absence of Transforming Growth Factor-β Signaling: ChIPSeq

Project description:CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity. Crucial for T helper17 (Th17) cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification. Herein, we show that Th17 differentiation occurs in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 in the absence of TGF-β1 were more pathogenic in this experimental disease. These data suggest a new model for Th17 differentiation. Consistent with genetic data linking the IL23R with autoimmunity, our findings re-emphasize the role of IL-23 and therefore have important implications for the development of new therapies. Examination of Stat3 binding and H3K4me and H3Ac in helper T cells.

2010-08-31 | E-GEOD-23681 | biostudies-arrayexpress

CUT&RUN experiment at four time points in HEK293T and hESC cells, assessing the time-resolved response of β-catenin genomic occupancy upon Wnt signaling activation

Project description:Wnt/β-catenin signaling is a highly organized biochemical cascade that triggers a gene expression program in the signal-receiving cell. The Wnt/β-catenin-driven transcriptional response is involved in virtually all cellular processes during development, homeostasis, and its deregulation causes human disease. However, outstanding questions remain unanswered. A first question concerns cell-specificity: how this response is integrated into lineage-specific choices is still unknown. A second question concerns time: it is not known whether β-catenin associates with its targets simultaneously or in a time-dependent fashion. For instance, while TCF/LEF and other components of the Wnt transcriptional complex are constitutively associated with the chromatin, it is β-catenin arrival, upon Wnt induction, that launches target genes transcription. Therefore, discovering the dynamics of the genome-wide β-catenin binding pattern is required to unambiguously define the direct targets of Wnt signaling To address these questions, we realized a time-resolved atlas of β-catenin genome-wide occupancy in two human cell types, human embryonic kidney cells 293T (HEK293T) and human embryonic stem cells (hESCs). To this end, we treated HEK293T and hESCs with the GSK3 inhibitor/Wnt activator CHIR99021 (10 mM) for 3 days, and assessed β-catenin binding via CUT&RUN-LoV-U (Zambanini et al., 2022) 90 minutes, 4 hours, 24 hours and 3 days after the onset of the stimulation. This approach allowed us to establish that β-catenin repositions to different genomic loci along stimulation time, showing that a definition of Wnt target genes must take into account the time-dimension. Moreover, β-catenin physical targets are largely cell-type specific, as only a subset of them is present across the examined contexts.

2022-09-30 | E-MTAB-12077 | biostudies-arrayexpress

Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function

Project description:This SuperSeries is composed of the following subset Series: GSE34018: Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [Expression array] GSE34019: Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [ChIP_seq] Refer to individual Series

2012-03-28 | E-GEOD-34020 | biostudies-arrayexpress

Inhibition of Androgen Receptor and β-catenin activity in prostate cancer

Project description:Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective new approach to treating prostate cancer. Here we provide proof-of-concept that a small molecule inhibitor of nuclear β-catenin activity (called C3) can inhibit both the AR and β-catenin signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both β-catenin/TCF and β-catenin/AR protein interaction, reflecting the fact that TCF and AR have overlapping binding sites on β-catenin. Given that AR interacts with, and is transcriptionally regulated by β-catenin, C3 treatment also resulted in decreased occupancy of β-catenin on the AR promoter and diminished AR and AR/β-catenin target gene expression. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and β-catenin cofactor, CARM1, providing new insight into the unrecognized function of β-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model, and blocked renewal of bicalutamide-resistant sphere forming cells, indicating the therapeutic potential of this approach. Compare and contrast the expression profile of prostate cancer cells treated with a Wnt inhibitor (C3) with respect to β-catenin and AR knockdown (all samples in duplicates).

2014-01-23 | E-GEOD-49295 | biostudies-arrayexpress

Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [ChIP_seq]

Project description:The circadian clock acts at the genomic level to coordinate internal behavioral and physiologic rhythms via the CLOCK-BMAL transcriptional heterodimer. Although the nuclear receptors REV-ERBα and β have been proposed to contribute to clock function, their precise roles and importance remain unresolved. To establish their regulatory potential we generated comparative cistromes of both Rev-erb isoforms, which revealed shared recognition at over ~50% of their total sites and extensive overlap with the master clock regulator Bmal. While Rev-erbα has been shown to directly regulate Bmal expression, the cistromic analysis reveals a more profound connection between Bmal and Rev-erbα and β regulatory circuits than previously suspected. Genes within the intersection of the Bmal and Rev-erb cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erbα/β function by creating double-knockout mice (DKOs) profoundly disrupted circadian expression of core clock and lipid homeostatic genes. As a result, DKOs show strikingly altered circadian wheel-running behavior and deregulated lipid metabolism. These data reveal an integral role of Rev-erbα/β in clock function as well as provide a cistromic basis for the integration of circadian rhythm and metabolism. Identification of Reverb alpha and Reverb beta binding sites in mouse liver at ZT8

2012-03-28 | E-GEOD-34019 | biostudies-arrayexpress

CUT&RUN LoV-U of beta-catenin, TCF/LEF transcription factors and histone modifications in HEK293T and mouse embryonic hindlimb tissue at 11.5 days post coitum

Project description:In our attempts to profile different regulators of the WNT/b-catenin transcriptional complex, CUT&RUN failed to produce consistent binding patterns of the non-DNA-binding b-catenin. We developed a modified CUT&RUN protocol, which we refer to as LoV-U (Low Volume and Urea), that enables the generation of robust and reproducible b-catenin binding profiles. CUT&RUN-LoV-U can profile all classes of chromatin regulators tested, as shown by datasets targeting the TCF/LEF transcription factors and various histone modifications. CUT&RUN-LoV-U uncovers direct WNT/β-catenin target genes in human cells, as well as in ex vivo cells isolated from developing mouse tissue.

2022-07-16 | E-MTAB-11951 | biostudies-arrayexpress

ChIP-seq analysis of CTCF binding sites in lymphocyte subsets

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2012-12-03 | E-GEOD-41743 | biostudies-arrayexpress

ATAC-seq experiment at four time points in HEK293 and hESC cells, assessing the time-resolved response on chromatin accessibility upon Wnt/β-catenin signaling activation

Project description:Wnt/β-catenin signaling is a highly organized biochemical cascade that triggers a gene expression program in the signal-receiving cell. The Wnt/β-catenin -driven transcriptional response is involved in virtually all cellular processes during development, homeostasis, and its deregulation causes human disease. However, outstanding questions remain unanswered. Among these, one regards how the Wnt/β-catenin cascade modulates the chromatin behavior: to date, there exists no comprehensive genome-wide annotation of changing chromatin patterns upon Wnt pathway activation. This is important, as shifts in chromatin patterns might underlie how different cells promote diverging gene expression programs in response to Wnt. To address this question, we characterized how Wnt/β-catenin signaling shapes the genome-wide chromatin accessibility landscape in two human cell types, human embryonic kidney cells 293T (HEK293T) and human embryonic stem cells (hESCs), over time. To this end, we treated HEK293T and hESCs with the GSK3 inhibitor/Wnt activator CHIR99021 (10 mM) for 3 days and assessed chromatin accessibility via ATAC-sequencing 4 hours, 24 hours and 3 days after the onset of the stimulation. We found that hESCs respond to Wnt/β-catenin activation by progressively shaping their chromatin accessibility profile in a manner that is consistent with their gradual acquisition of a mesodermal identity: differentiation genes loci open over time, while pluripotency ones close. We refer to this genomic response as plastic. On the other hand, HEK293T, which are known to be highly responsive to Wnt activation, appear more resistant to a long-term Wnt/β-catenin-driven change in cell identity. In this context, the chromatin displays a temporary opening of relevant regions at 4 hours after stimulation, followed by a re-establishment of its pre-stimulation state: we define this transient response as elastic.

2022-09-30 | E-MTAB-12076 | biostudies-arrayexpress

ChIP-seq analysis of CTCF binding sites in lymphocyte subsets [DP thymocytes]

Project description:In this study, we compare the binding pattern of CTCF at the T cell receptor alpha locus in different subsets of developing lymphocytes For the ChIP-seq, input and immunoprecipitated DNA was given to The Scripps DNA Array Facility, where it was prepared for massively parallel sequencing on Illumina Genome Analyzer IIx.

2012-12-03 | E-GEOD-41740 | biostudies-arrayexpress

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