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Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling (RNA-seq data set)

ABSTRACT: Gene expression profiling of Pygo2 mutant branchyal arches (BA) and developing heart tubes at 10.5 days post coitum

ORGANISM(S): Mus musculus

PROVIDER: GSE110782 | GEO | 2021/02/14

REPOSITORIES: GEO

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Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling (ChIP-seq data set)

Project description:Genome-wide DNA binding profiles of the components of the Wnt signaling transcriptional complex, beta-catenin and Pygo2, in mouse developing branchyal arches (BA) and looping heart.

2021-02-14 | GSE110781 | GEO

Mutations in <i>Bcl9</i> and <i>Pygo</i> genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling.

Project description:Bcl9 and Pygopus (Pygo) are obligate Wnt/β-catenin cofactors in Drosophila, yet their contribution to Wnt signaling during vertebrate development remains unresolved. Combining zebrafish and mouse genetics, we document a conserved, β-catenin-associated function for BCL9 and Pygo proteins during vertebrate heart development. Disrupting the β-catenin-BCL9-Pygo complex results in a broadly maintained canonical Wnt response yet perturbs heart development and proper expression of key cardiac regulators. Our work highlights BCL9 and Pygo as selective β-catenin cofactors in a subset of canonical Wnt responses during vertebrate development. Moreover, our results implicate alterations in BCL9 and BCL9L in human congenital heart defects.

| S-EPMC6217730 | biostudies-literature

RNA-seq experiment of developing mouse forelimbs, comparing Bcl9/9l mutant with control littermates.

Project description:Forelimbs were manually dissected from three individual Bcl9/9l-deltaHD1/deltaHD2 mutants and three control littermates, at 10.5 days post coitum. BCL9 and BCL9L are paralogous beta-catenin cofactors involved in the transcriptional machinery of Wnt target genes.

2020-05-08 | E-MTAB-9000 | biostudies-arrayexpress

Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-02-14 | GSE110783 | GEO

Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling

Project description:A CRISPR-Cas9-based zebrafish screen for candidate genes causative of human heart disease uncovers cardiac defects when perturbing Bcl9.

2020-12-15 | GSE108240 | GEO

Decoding of methylated histone H3 tail by the Pygo-BCL9 Wnt signaling complex.

Project description:Pygo and BCL9/Legless transduce the Wnt signal by promoting the transcriptional activity of beta-catenin/Armadillo in normal and malignant cells. We show that human and Drosophila Pygo PHD fingers associate with their cognate HD1 domains from BCL9/Legless to bind specifically to the histone H3 tail methylated at lysine 4 (H3K4me). The crystal structures of ternary complexes between PHD, HD1, and two different H3K4me peptides reveal a unique mode of histone tail recognition: efficient histone binding requires HD1 association, and the PHD-HD1 complex binds preferentially to H3K4me2 while displaying insensitivity to methylation of H3R2. Therefore, this is a prime example of histone tail binding by a PHD finger (of Pygo) being modulated by a cofactor (BCL9/Legless). Rescue experiments in Drosophila indicate that Wnt signaling outputs depend on histone decoding. The specificity of this process provided by the Pygo-BCL9/Legless complex suggests that this complex facilitates an early step in the transition from gene silence to Wnt-induced transcription.

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Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models.

Project description:Bcl9 and Pygo are Wnt enhanceosome components that effect ?-catenin-dependent transcription. Whether they mediate ?-catenin-dependent neoplasia is unclear. Here we assess their roles in intestinal tumourigenesis initiated by Apc loss-of-function (ApcMin), or by Apc1322T encoding a partially-functional Apc truncation commonly found in colorectal carcinomas. Intestinal deletion of Bcl9 extends disease-free survival in both models, and essentially cures Apc1322T mice of their neoplasia. Loss-of-Bcl9 synergises with loss-of-Pygo to shift gene expression within Apc-mutant adenomas from stem cell-like to differentiation along Notch-regulated secretory lineages. Bcl9 loss also promotes tumour retention in ApcMin mice, apparently via relocating nuclear ?-catenin to the cell surface, but this undesirable effect is not seen in Apc1322T mice whose Apc truncation retains partial function in regulating ?-catenin. Our results demonstrate a key role of the Wnt enhanceosome in ?-catenin-dependent intestinal tumourigenesis and reveal the potential of BCL9 as a therapeutic target during early stages of colorectal cancer.

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Structural basis of the interaction between BCL9-Pygo and LDB-SSBP complexes in assembling the Wnt enhanceosome.

Project description:The Wnt enhanceosome is responsible for transactivation of Wnt-responsive genes and a promising therapeutic target for treatment of numerous cancers with Adenomatous Polyposis Coli (APC) or β-catenin mutations. How the Wnt enhanceosome is assembled remains poorly understood. Here we show that B-cell lymphoma 9 protein (BCL9), Pygopus (Pygo), LIM domain-binding protein 1 (LDB1) and single-stranded DNA-binding protein (SSBP) form a stable core complex within the Wnt enhanceosome. Their mutual interactions rely on a highly conserved N-terminal asparagine proline phenylalanine (NPF) motif of Pygo, through which the BCL9-Pygo complex binds to the LDB-SSBP core complex. Our crystal structure of a ternary complex comprising the N-terminus of human Pygo2, LDB1 and SSBP2 reveals a single LDB1-SSBP2 complex binding simultaneously to two Pygo2 molecules via their NPF motifs. These interactions critically depend on the NPF motifs which bind to a deep groove formed between LDB1 and SSBP2, potentially constituting a binding site for drugs blocking Wnt/β-catenin signaling. Analysis of human cell lines lacking LDB or Pygo supports the functional relevance of the Pygo-LDB1-SSBP2 interaction for Wnt/β-catenin-dependent transcription.

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Transcriptomic analyses of 11.5 dpc female germ cell (mouse) exposed or not to Bisphenol A analogues (BPAF and BADGE)

Project description:Pregnant mice were orally exposed to 10-5 M of bisphenolA analogs (BPAF and BADGE) from 10.5 day post-coitum (dpc) to 11.5 dpc. SSEA1 positive female germ cells from bisphenols- or vehicule- (ethanol) treated ovaries were collected. RNA were submitted to microarrays.

2022-04-01 | E-MTAB-9344 | biostudies-arrayexpress

Transcriptomic analyses of 13.5 dpc female germ cell (mouse) exposed or not to Bisphenol A analogues (BPAF and BADGE)

Project description:Pregnant mice were orally exposed to 10-5 M of bisphenolA analogs (BPAF and BADGE) from 10.5 day post-coitum (dpc) to 13.5 dpc. 13.5 dpc SSEA1 positive female germ cells from bisphenols- or vehicule- (ethanol) treated ovaries were collected. RNA were submitted to microarrays.

2022-04-01 | E-MTAB-9401 | biostudies-arrayexpress

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