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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Identification of beta-catenin-associated RNAs in myeloid leukaemia cells through RIP-seq

ABSTRACT: Myeloid cell lines (K562 and HEL) were treated overnight with CHIR99021 or a vehicle control (DMSO). CHIR99021 treatment inhibits GSK3B within the destruction complex functioning in Wnt/beta-catenin signalling pathway, thereby preventing beta-catenin degradation and promoting its stabilization. Following the overnight incubation, beta-catenin RIP (RNA immunoprecipitation) was performed in both K562 and HEL cells. RNA samples obtained from beta-catenin RIP in these cells were then sequenced to identify beta-catenin-associated RNAs under CHIR99021 treatment compared to basal conditions (DMSO control).

INSTRUMENT(S): NextSeq 500, 75 bp single end lane, NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER: M Wagstaff

PROVIDER: E-MTAB-14675 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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β-Catenin interacts with canonical RBPs including MSI2 to associate with a Wnt signalling mRNA network in myeloid leukaemia cells.

Wagstaff M M Sevim O O Goff A A Raynor M M Park H H Mancini E J EJ Nguyen D T T DTT Chevassut T T Blair A A Castellano L L Newbury S S Towler B B Morgan R G RG

Oncogene 20250430 29

Wnt/β-catenin signalling is important for normal hematopoietic stem/progenitor cell (HSPC) biology and heavily implicated in acute and chronic myeloid leukaemia (AML and CML). The central mediator β-catenin is an attractive therapeutic target in myeloid neoplasms however its targeting has been hampered by a poor characterisation of its molecular interactions in haematopoietic cells, which will differ from its network in solid tissues. Our previous β-catenin interactome study identified the signi ...[more]

PMID: 40301545

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Characterisation of the Beta-Catenin cytoplasmic/nuclear interactome in leukaemia cells

Project description:Canonical Wnt/B-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia (AML) patients; however, some patients exhibit little or no β-catenin nuclear-localization even where cytosolic B-catenin is abundant. Differential propensity for nuclear-localized β-catenin is also observed in cell lines. To investigate the factors mediating the nuclear-localization of B-catenin we carried out a nuclear/cytoplasmic proteomic analysis of the B-catenin interactome in myeloid leukemia cells. From this we identified hundreds of putative novel B-catenin-interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear B-catenin, K562/HEL) versus Wnt-unresponsive cells (low nuclear B-catenin, ML1) suggested the established interactor, LEF1, is a key factor mediating the nuclear-localization of B-catenin in myeloid leukemia. The relative levels of nuclear LEF1 and B-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF1 knockdown inhibited B-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF1 overexpression was able to promote both nuclear-localization and B-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This study is the first to present a B-catenin interactome in hematopoietic cells and reveals LEF1 as a critical regulator of canonical Wnt signaling in myeloid leukemia.

2019-01-11 | PXD009305 | Pride

cDNA microarray Analysis of human iPSC-derived mesodermal progenitors treated with CHIR99021 compared to controls

Project description:The aim of this study was to unravel the effects of an initial WNT/β-catenin pulse on the in vitro differentiation of human iPSCs towards mesodermal progenitors and subsequent specification of chondrocytes. Therefore, mesodermal progenitors were generated from hiPSCs according to standard protocol (ctrl) or treated with 5 µM WNT/β-catenin agoinst CHIR99021 for 24h. To understand the long-term effects of short-initial WNT pulse on mesodermal differentiation, the global gene expression profile of day 14 mesodermal progenitors was compared.

2020-12-31 | E-MTAB-9226 | biostudies-arrayexpress

Identification of beta-catenin binding regions in SW480 cells

Project description:Deregulation of canonical Wnt/beta-catenin pathway is one of the earliest events in the pathogenesis of colon cancer. Mutations in APC or CTNNB1 (beta-catenin gene) are highly frequent in colon cancer and cause aberrant stabilization of b-catenin, which activates the transcription of Wnt target genes by binding to chromatin via the TCF/LEF transcription factors. Here we report an integrative analysis of genome-wide chromatin occupancy of b-catenin by chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) and gene expression profiling by microarray analysis upon RNAi-mediated knockdown of beta-catenin in colon cancer cells (GSE53656). Immunoprecipitated samples from human colon cancer SW480 cells with antibodies against beta-catenin and control IgG respectively were used for ChIP-seq experiments.

2014-03-12 | E-GEOD-53927 | biostudies-arrayexpress

Transcriptional responses to GSK3 inhibitor and MEK inhibitor on 2i-adapted mouse embryonic stem cells

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2013-03-01 | E-GEOD-43421 | biostudies-arrayexpress

ATAC-seq time-course profiling upon Wnt stimulation in ΔCTNNB1 HEK293T cells

Project description:Wnt/β-catenin signaling is generally thought to activate transcription primarily through pre-accessible regulatory elements. However, we previously identified cases in which β-catenin associates with initially inaccessible chromatin regions that subsequently gain accessibility (E-MTAB-12076, Pagella et. al., (2023) Cell Systems). To determine whether stimulus-dependent chromatin opening requires β-catenin, we performed ATAC-seq in β-catenin knockout (ΔCTNNB1) human embryonic kidney 293T (HEK293T) cells, both prior to and 4 hours following pathway activation.

2026-05-24 | E-MTAB-16975 | biostudies-arrayexpress

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Project description:To validate the suitability of two commonly used colorectal cancer cell lines, DLD1 and SW480, as model systems to study colorectal carcinogenesis, we treated these cell lines with beta-catenin siRNA and identified beta-catenin target genes using DNA microarrays. The list of identified target genes was compared to previously published beta-catenin target genes found in the PubMed and the GEO databases. Based on the large number of beta-catenin target genes found to be similarly regulated in DLD1, SW480 and LS174T as well as the large overlap with confirmed β-catenin target genes, we conclude that DLD1 and SW480 colon carcinoma cell lines are suitable model systems to study beta-catenin regulated genes and signaling pathways 12 arrays (2 cell lines, 2 treatments, 3 biological replicates)

2013-12-31 | E-GEOD-44097 | 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

FOXO3a and beta-catenin transcriptional profile in human colon cancer cell line DLD1

Project description:We established a model system in human DLD1 colon cancer cells to study the transcriptional crosstalk between FOXO3A and beta-Catenin. Thereby, translocation to the nucleus of a AKT-insensitive mutant (T32A, S253A, S315A) of human FOXO3A fused to the ligand binding domain of human estrogen receptor can be induced by exposure to 4-hydroxy-tamoxifen. Furthermore, expression of a stable mutant (S33Y) of human beta-catenin is doxycycline inducible. Addition of those drugs separately or in combination allows identification of common or excusive target gene sets.

2012-05-01 | E-MEXP-3262 | biostudies-arrayexpress

Human platelet β-catenin interaction proteome

Project description:In nucleated cells, β-catenin, the key downstream effector of this pathway, is a dual function protein, regulating the coordination of gene transcription and cell–cell adhesion. The specific role of β-catenin in the anucleate platelet however remains elusive. Here, we performed a label-free quantitative proteomic analysis of β-catenin immunoprecipitates from human platelets identifying 9 co-immunoprecipitating proteins. GO biological pathway analysis revealed a significant enrichment of specific functional terms including 'cell adhesion', 'cell junction organization' and ‘adherens junction organization'. Our bioinformatics data suggests that human platelet β-catenin may be involved in facilitating cell adhesion and cell junctions. We found three proteins co-immunoprecipitating with β-catenin under both resting and activated conditions, four proteins under resting condition only and two proteins under activated condition only.

2018-07-05 | PXD008130 | Pride

TCF/LEF dependent and independent regulation of Wnt/beta-catenin transcription

Project description:During canonical Wnt signalling the activity of nuclear beta-catenin is largely mediated by the TCF/LEF family of transcription factors. To challenge this view we used the CRISPR/Cas9 genome editing approach to generate HEK 293T cell clones simultaneously carrying loss-of-function alleles of all four TCF/LEF genes. Exploiting unbiased whole transcriptome sequencing studies, we found that a subset of beta-catenin transcriptional targets did not require TCF/LEF factors for their regulation. Consistent with this finding, we observed in a genome-wide analysis that beta-catenin occupied specific genomic regions in the absence of TCF/LEF. Finally, we revealed the existence of a transcriptional activity of beta-catenin that specifically appears when TCF/LEF factors are absent, and refer to this as beta-catenin-GHOST response. Collectively, this study uncovers a previously neglected modus operandi of beta-catenin that bypasses the TCF/LEF transcription factors.

2018-11-22 | E-MTAB-7028 | biostudies-arrayexpress

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