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Characterization of the effects of ISX9 treatment on RBPJ target genes. [ATAC-Seq]

ABSTRACT: The Notch signaling pathway regulates several processes including development and differentiation and its aberrant regulation leads to several diseases. The transciption factor RBPJ is the main mediator of the Notch signaling pathway, regulating both repression and activation of Notch target gens. Here, we first identified RBPJ target genes by analyzing the transcriptional effects of RBPJ depletion and the binding of RBPJ by ChIP-Seq in H1299 cells. Subsequently, we analyzed the gene expression profile upon 12 or 24 hours ISX9 treatment in H1299 cells focusing on the identified RBPJ target genes. Finally, we analyzed the effects of 12 hours ISX9 treatment on the chromatin in H1299 cells by performing ChIP-Seq versus H3K4me1, H3K4me3 and H3K27ac.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288439 | GEO | 2026/06/24

REPOSITORIES: GEO

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Characterization of the effects of ISX9 treatment on RBPJ target genes. [ChIP-Seq]

Project description:The Notch signaling pathway regulates several processes including development and differentiation and its aberrant regulation leads to several diseases. The transciption factor RBPJ is the main mediator of the Notch signaling pathway, regulating both repression and activation of Notch target gens. Here, we first identified RBPJ target genes by analyzing the transcriptional effects of RBPJ depletion and the binding of RBPJ by ChIP-Seq in H1299 cells. Subsequently, we analyzed the gene expression profile upon 12 or 24 hours ISX9 treatment in H1299 cells focusing on the identified RBPJ target genes. Finally, we analyzed the effects of 12 hours ISX9 treatment on the chromatin in H1299 cells by performing ChIP-Seq versus H3K4me1, H3K4me3 and H3K27ac.

2026-06-24 | GSE288448 | GEO

Characterization of the effects of ISX9 treatment on RBPJ target genes. [RNA-Seq]

2026-06-24 | GSE288438 | GEO

RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1

Project description:Notch signaling is an evolutionarily conserved signal transduction pathway that is essential for metazoan development. At the molecular level, the key components of the Notch pathway are the NOTCH-family receptors, the ligands of the DSL (Delta, Serrate, Lag-2) family and the transcription factor CSL [CBF1/RBPJ, Su(H), Lag-1]. Upon ligand binding, the NOTCH Intra-Cellular Domain (NOTCH ICD) translocates into the nucleus and forms a complex with RBPJ to activate the transcription of target genes. In the absence of NOTCH ICD, RBPJ acts as a transcriptional repressor. Using a proteomic approach, we identified L3MBTL3 as a novel interactor of RBPJ. We discovered that L3MBTL3 competes with NOTCH ICD for binding to RBPJ. In the absence of NOTCH ICD, RBPJ recruits L3MBTL3 and its co-factor KDM1A [lysine (K)-specific demethylase 1A] to the promoters/enhancers of Notch target genes to promote H3K4me2 demethylation and transcriptional repression. In three distinct cell contexts in which Notch signaling governs cell fate, i.e., mature T-cells as well as brain and breast tumor cells, the loss of L3MBTL3 results in the de-repression of Notch target genes. Finally, the genetic analyses of the homologs of RBPJ and L3MBTL3 in Drosophila melanogaster and Caenorhabditis elegans demonstrate that the functional link between RBPJ/Su(H)/lag-1 and L3MBTL3/dL(3)mbt/lin-61 is evolutionarily conserved, thus identifying L3MBTL3 as a universal modulator of Notch signaling in metazoans.

2017-10-17 | PXD004196 | Pride

Comparative studies of RNAs in GICs and ISX9-treated GICs

Project description:To identify genes that increase or decreaes in ISX9-treated GICs, we compare the expression levels of RNAs in ISX9-treated GICs with those in GICs.

2026-04-01 | GSE325091 | GEO

FBXO42 facilitates Notch signaling activation and global chromatin relaxation by promoting K63-linked polyubiquitination of RBPJ

Project description:Dysregulation of the Notch-RBPJ signaling pathway has been found associated with various human diseases including cancers; however, precisely how this key signaling pathway is fine-tuned via its interactors and modifications is still largely unknown. In this study, using a proteomic approach, we identified FBXO42 as a novel RBPJ interactor. FBXO42 promotes RBPJ polyubiquitination on lysine (K) 175 via K63 linkage, which enhances the association of RBPJ with chromatin remodeling complexes and induces a global chromatin relaxation. Genetically depleting FBXO42 or pharmacologically targeting its E3 ligase activity attenuates the Notch signaling-related leukemia development in vivo. Taken together, our findings not only revealed FBXO42 as a critical regulator of the Notch pathway by modulating RBPJ-dependent global chromatin landscape changes, but also provide insights into the therapeutic intervention of the Notch pathway for leukemia treatment.

2022-10-13 | PXD034938 | Pride

RNA-seq Profiles in RBPJ Maintains Brain Tumor Initiating Cells through CDK9-mediated Transcriptional Elongation

Project description:Glioblastomas coopt stem cell regulatory pathways to maintain brain tumor initiating cells (BTICs), also known as cancer stem cells. Notch signaling has been a molecular target in BTICs, but Notch antagonists have demonstrated limited efficacy in clinical trials. RBPJ is considered a central transcriptional mediator of Notch activity. Here, we report that pharmacologic Notch inhibitors were less effective than targeting RBPJ in suppressing tumor growth. While Notch inhibitors decreased canonical Notch gene expression, RBPJ regulated a distinct profile of genes critical to BTIC stemness and cell cycle progression. RBPJ was preferentially expressed by BTICs and required for BTIC self-renewal and tumor growth. MYC, a key BTIC regulator, bound the RBPJ promoter and treatment with a BET family bromodomain inhibitor decreased MYC and RBPJ expression. Proteomic studies demonstrated that RBPJ binds CDK9, a component of P-TEFb (positive transcription elongation factor), to target gene promoters, enhancing transcriptional elongation. Collectively, RBPJ links MYC and transcriptional control through CDK9, providing potential nodes of fragility for therapeutic intervention, potentially distinct from Notch.

2016-05-01 | GSE79735 | GEO

Dynamic binding of RBPJ is determined by Notch signalling status

Project description:Notch signalling plays crucial roles in mediating cell fate choices in all metazoans largely by specifying the transcriptional output of one cell in response to a neighbouring cell. The DNA-binding protein RBPJ is the principle effector of this pathway in mammals and together with the transcription factor moiety of Notch (NICD) it regulates the expression of target genes. The prevalent view presumes that RBPJ statically occupies consensus binding sites while exchanging repressors for activators in response to NICD. We present the first specific RBPJ chromatin immunoprecipitation and high-throughput sequencing study in mammalian cells. To dissect the mode of transcriptional regulation by RBPJ and identify its direct targets, whole genome binding profiles were generated for RBPJ, its coactivator p300, NICD and the histone H3 modifications H3K4me3, H3K4me1 and H3K27ac in myogenic cells under active or inhibitory Notch signalling conditions. Our results demonstrate dynamic binding of RBPJ in response to Notch activation at essentially all sites co-occupied by NICD. Additionally, we identify a distinct set of sites where RBPJ recruits neither NICD nor p300, and binds DNA statically, irrespective of Notch activity. These findings significantly modify our views on how RBPJ and Notch signalling mediate their activities and consequently impact on cell fate decisions. ChIP (chromatin immunoprecipitation) is followed by deep sequencing to generate genome-wide patterns of RBP-J binding in mouse C2C12 cells under various conditions. Cells were either Notch activated by exposure to immobilized ligand or by overexpression of NICDGFP, or Notch inhibited by treatment with DAPT. Notch activation and inhibition treatments were applied for 6h and 24h. In addition to RBP-J, p300 and NICDGFP were profiled by ChIP-Seq and gene expression was assessed by RNA-Seq.

2013-05-13 | E-GEOD-37184 | biostudies-arrayexpress

Messenger RNA expression profiling in L3mbtl3 WT versus L3mbtl3 KO/+ mouse cerebella.

Project description:The NOTCH/RBPJ pathway governs cell proliferation in many biological contexts, including SHH and Group#3 medulloblastoma (MB) tumorigenesis. Using our proteomic platform, we discovered an interaction between RBPJ, a key co-factor of NOTCH for the modulation of the NOTCH/RBPJ signaling pathway, and L3MBTL3, a methyllysine reader. L3MBTL3 is recruited by RBPJ on chromatin at the enhancers of NOTCH/RBPJ target genes to repress their expression. Deletions of the L3MBTL3 locus are observed in patients with WNT and Group#3 MB and expression of L3MBTL3 in the SHH MB-derived cell DAOY inhibits cell growth, suggesting a putative tumor suppressor role for L3MBTL3 in MB. To further investigate the putative role of L3MBTL3 as a suppressor of MB tumorigenesis, we explored the transcriptome of L3mbtl3 KO mouse cerebella using RNA-seq.

2021-05-28 | GSE151448 | GEO

Dynamic binding of RBPJ is determined by Notch signalling status

2013-05-13 | GSE37184 | GEO

Effect on small molecule RBPJ inhibitor (RIN1) on gene expression in Jurkat cells compared to gamma secretase inhibition and siRNA knockdown of RBPJ

Project description:We discovered a new class of small molecule inhibitor that disrupts the interaction between NOTCH and RBPJ, which is the main transcriptional effector of NOTCH signaling. RBPJ Inhibitor-1 (RIN1) also blocked the functional interaction of RBPJ with SHARP, a scaffold protein that forms a transcriptional repressor complex with RBPJ in the absence of NOTCH signaling. RIN1 induced changes in gene expression resembled siRNA silencing of RBPJ rather than inhibition at the level of NOTCH itself. RIN1 inhibits RBPJ in its repressing and activating contexts.

2019-07-18 | GSE134401 | GEO

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