Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Characterization of Notch transcription complex sequence paired sites

ABSTRACT: Notch transcription complexes (NTCs) drive target gene expression by binding to two distinct types of genomic response elements, NTC monomer-binding sites and sequence-paired sites (SPSs) that bind NTC dimers. SPSs are conserved and are linked to the Notch-responsiveness of a few genes, but their overall contribution to Notch-dependent gene regulation is unknown. To address this issue, we determined the DNA sequence requirements for NTC dimerization using a fluorescence resonance energy transfer (FRET) assay, and applied insights from these in vitro studies to Notch-“addicted” leukemia cells. We find that SPSs contribute to the regulation of approximately a third of direct Notch target genes. While originally described in promoters, SPSs are present mainly in long-range enhancers. Our work provides a general method for identifying sequence-paired sites in genome-wide data sets and highlights the widespread role of NTC dimerization in Notch-transformed leukemia cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE97465 | GEO | 2017/04/07

SECONDARY ACCESSION(S): PRJNA381917

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Mus musculus

Project description:Characterization of Notch transcription complex sequence paired sites

| PRJNA381917 | ENA

Aberrant homeodomain-DNA cooperative dimerization underlies distinct developmental defects in two dominant CRX retinopathy models [MPRA]

Project description:Paired-class homeodomain transcription factors (HD TFs) play essential roles in vertebrate development, and their mutations are linked to human diseases. One unique feature of paired-class HD is cooperative dimerization on specific palindrome DNA sequences. Yet, the functional significance of HD cooperative dimerization in animal development and its dysregulation in diseases remain elusive. Using the retinal TF Cone-rod Homeobox (CRX) as a model, we have studied how blindness-causing mutations in the paired HD, p.E80A and p.K88N, alter CRX’s cooperative dimerization, lead to gene misexpression and photoreceptor developmental deficits in dominant manners. CRXE80A maintains binding at monomeric WT CRX motifs but is deficient in cooperative binding at dimeric motifs. CRXE80A’s dimerization defect impacts the exponential increase of photoreceptor gene expression in terminal differentiation and produces immature, non-functional photoreceptors in the CrxE80A retinas. CRXK88N is highly cooperative and localizes to ectopic genomic sites with strong enrichment of dimeric HD motifs. CRXK88N’s altered biochemical properties disrupt CRX’s ability to direct dynamic chromatin remodeling during development to activate photoreceptor differentiation programs and silence progenitor programs. Our study here provides in vitro and in vivo molecular evidence that paired-class HD cooperative dimerization regulates neuronal development and dysregulation of cooperative binding contributes to severe dominant blinding retinopathies.

2024-11-22 | GSE256214 | GEO

Aberrant homeodomain-DNA cooperative dimerization underlies distinct developmental defects in two dominant CRX retinopathy models [Coop-seq]

2024-11-22 | GSE256213 | GEO

Aberrant homeodomain-DNA cooperative dimerization underlies distinct developmental defects in two dominant CRX retinopathy models [ATAC-seq]

2024-11-22 | GSE256212 | GEO

NOTCH dimerization contributes to maintenance of intestinal homeostasis

Project description:NOTCH dimerization contributes to maintenance of intestinal homeostasis

| PRJNA1091961 | ENA

CBFA2T3-GLIS2 Mediates Transcriptional Regulation of Developmental Pathways through a Gene Regulatory Network

Project description:CBFA2T3-GLIS2 is a fusion oncogene found in pediatric acute megakaryoblastic leukemia (AMKL) that is associated with a poor prognosis. We established a model of CBFA2T3-GLIS2 driven AMKL that allows the distinction of fusion specific changes from those that reflect the megakaryoblast lineage of this leukemia. Using this model, we mapped genome wide binding that in turn imparts the characteristic transcriptional signature. A network of transcription factor genes bound and upregulated by the fusion were found to have downstream effects that result in dysregulated signaling of developmental pathways including NOTCH, Hedgehog, TGF, and WNT. Transcriptional regulation is mediated by homo-dimerization and binding of the ETO transcription factor through the nervy homology region 2 (NHR2). Loss of NHR2 abrogated the development of leukemia and led to the downregulation of JAK/STAT and NOTCH transcriptional signatures. These data contribute to the understanding of CBFA2T3-GLIS2 mediated leukemogenesis and identify potential therapeutic vulnerabilities for future studies.

2024-08-30 | GSE219269 | GEO

Mapping of Ikaros and RBPJ binding sites in the mouse T cell leukemia cell line T29

Project description:The transcription factor Ikaros represses Notch signaling. Since Ikaros and Notch treanscriptional mediator RBPJ both recognize sequences that contain the same core TGGGAA motif, it was hypothesized that Ikaros represses Notch signaling by targeting Notch response elements and competing with RBPJ for their binding. Here we used the mouse T-cell leukemia cell line T29 to compare the genomic binding profiles of Ikaros and RBPJ by ChIP-seq. The T29 cell line is derived from a Ikaros-deficient T-cell leukemia (Dumortier et al, MCB 26, 209-220, 2006) and exhibits strong Notch activation. We performed two chip-seq experiments with an anti-RBPJ antibody to map RBPJ binding sites. To map Ikaros binding sites, we engineered a T29-derived cell line that expresses a fusion protein between Ikaros and the ligand binding domain of the estrogen receptor (Ik1-ER) which is activated by addition of 4-hydroxy-tamoxifen (4OHT). We used an anti-Ikaros antibody to map the sites bound by Ik1-ER after treatment of the cells with 4OHT. Sequencing were performed with the Illumina GAII sequencer as as single end 36 base pair reads.

2014-04-02 | E-GEOD-46119 | biostudies-arrayexpress

RNA-seq CELSR2 knockdown vs NTC

Project description:RNA-seq experiments in two B-lineage leukemia cell lines (NALM6 and 697) either 0hr prednisilone treated or 24hr prednisolone treated in either NTC or CELSR2 knockdown (240-1)

2020-01-23 | GSE115384 | GEO

Exposure to mites sensitizes intestinal stem cell maintenance, splenic marginal zone B cell homeostasis, and heart development to Notch dosage and cooperativity [RNA-seq]

Project description:Cooperative DNA binding is a key feature of transcriptional regulation. Here we examined the role of cooperativity in Notch signaling by CRISPR-mediated engineering of mice in which neither Notch1 nor Notch2 can homo- or heterodimerize, essential for cooperative binding to sequence paired sites (SPS) located near many Notch-regulated genes. While most known Notch-dependent phenotypes were unaffected in Notch1/2 dimer-deficient mice, a subset of tissues proved highly sensitive to loss of cooperativity. These phenotypes include heart development, compromising viability in combination with low gene dose, and the gut, developing ulcerative colitis in response to 1% DSS. The most striking phenotypes – gender imbalance and splenic marginal zone B cell lymphoma – emerged in combination with gene dose reduction or when challenged by chronic fur mite infestation. This study highlights the role of the environment in malignancy and colitis, and is consistent with Notch-dependent anti-parasite immune responses being compromised in the dimer deficient animals.

2020-05-15 | GSE149991 | GEO

Exposure to mites sensitizes intestinal stem cell maintenance, splenic marginal zone B cell homeostasis, and heart development to Notch dosage and cooperativity [ATAC-seq]

2020-05-15 | GSE149990 | GEO