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Haploinsufficiency of RREB1 causes a Noonan-like syndrome via epigenetic reprogramming of RAS-MAPK pathway genes.

ABSTRACT: RREB1 is an epigenetic regulator of the RAS-MAPK pathway genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146902 | GEO | 2020/03/13

REPOSITORIES: GEO

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Haploinsufficiency of RREB1 causes a Noonan-like syndrome via epigenetic reprogramming of RAS-MAPK pathway genes.

Project description:Haploinsufficiency of RREB1 causes a Noonan-like syndrome via epigenetic reprogramming of RAS-MAPK pathway genes.

| PRJNA612330 | ENA

Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigentic regulation of RAS-MAPK pathway genes.

Project description:Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigentic regulation of RAS-MAPK pathway genes.

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Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes.

Project description:RAS-MAPK signaling mediates processes critical to normal development including cell proliferation, survival, and differentiation. Germline mutation of RAS-MAPK genes lead to the Noonan-spectrum of syndromes. Here, we present a patient affected by a 6p-interstitial microdeletion with unknown underlying molecular etiology. Examination of 6p-interstitial microdeletion cases reveals shared clinical features consistent with Noonan-spectrum disorders including short stature, facial dysmorphia and cardiovascular abnormalities. We find the RAS-responsive element binding protein-1 (RREB1) is the common deleted gene in multiple 6p-interstitial microdeletion cases. Rreb1 hemizygous mice display orbital hypertelorism and cardiac hypertrophy phenocopying the human syndrome. Rreb1 haploinsufficiency leads to sensitization of MAPK signaling. Rreb1 recruits Sin3a and Kdm1a to control H3K4 methylation at MAPK pathway gene promoters. Haploinsufficiency of SIN3A and mutations in KDM1A cause syndromes similar to RREB1 haploinsufficiency suggesting genetic perturbation of the RREB1-SIN3A-KDM1A complex represents a new category of RASopathy-like syndromes arising through epigenetic reprogramming of MAPK pathway genes.

| S-EPMC7495420 | biostudies-literature

Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigentic regulation of RAS-MAPK pathway genes.

Project description:Whole genome analysis of mRNA transcripts regulated by RRBE1 in HEK293 cells.

2020-07-31 | GSE151417 | GEO

Effect of RREB1 knockdown using siRNA in A673 Ewing sarcoma cells (RNA-seq)

Project description:Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed EwS cases had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer, and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential, and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation.

2023-10-23 | GSE220780 | GEO

Drosophila CNS mitochondrial dysfunction with Ras/MAPK inhibition microarray

Project description:Mitochondrial dysfunction causes biophysical, metabolic and signalling changes that alter homeostasis and reprogram cells. We used a Drosophila model in which TFAM is overexpressed in the nervous system with or without Ras/MAPK pathway inhibition, by knock-down of the ETS transcription factor pointed, to investigate the how mitochondrial dysfunction and Ras/MAPK signalling affect the transcriptome. We used microarray analysis to investigate gene expression in cases of mitochondrial dysfunction in the CNS with or without Ras/MAPK pathway inhibition by knock-down of pointed (Pnt) and anterior open (Aop).

2018-05-05 | GSE114054 | GEO

Hyperactive RAS/MAPK introduces cancer-specific mitotic vulnerabilities

Project description:We performed tanscriptional profiling of ARPE19 and four isogenic transformed cells lines in which Ras or two downstream pathways, MAPK or PI3K/mTOR, were up-regulated. The purpose of this study is to understand how Ras signaling impacts kinetochore function.

2022-09-21 | GSE172512 | GEO

RNA-sequencing of Rreb1+/+ and Rreb1-/- embryonic day 7.5 mouse embryos

Project description:RNA-sequencing of Rreb1+/+ and Rreb1-/- embryonic day 7.5 mouse embryos

2021-04-21 | GSE148514 | GEO

Loss of primary cilia drives switching from Hedgehog to Ras/MAPK pathway

Project description:Basal cell carcinomas (BCCs) rely on Hedgehog (HH) pathway growth signal amplification by the microtubule-based organelle, the primary cilium. Despite naïve tumors responsiveness to Smoothened inhibitors (Smoi), resistance in advanced tumors remains frequent. While the resistant BCCs usually maintain HH pathway activation, squamous cell carcinomas with Ras/MAPK pathway activation also arise, with the molecular basis of tumor type and pathway selection still obscure. Here we identify the primary cilium as a critical determinant controlling tumor pathway switching. Strikingly, Smoi-resistant BCCs possess an increased mutational load in ciliome genes, resulting in reduced primary cilia and HH pathway activation compared to naive or Gorlin patient BCCs. Gene set enrichment analysis of resistant BCCs with a low HH pathway signature reveals increased Ras/MAPK pathway activation. Tissue analysis confirms an inverse relationship between primary cilia presence and Ras/MAPK activation, and primary cilia removal in BCCs potentiates Ras/MAPK pathway activation. Moreover, activating Ras in HH-responsive cell lines confers resistance to both canonical (vismodegib) and non-canonical (aPKC and MRTF inhibitors) HH pathway inhibitors, while conferring sensitivity to MAPK inhibitors. Our results provide new insights into BCC treatment and identify the primary cilium as an important lineage gatekeeper, preventing HH to Ras/MAPK pathway switching.

2018-10-10 | GSE120954 | GEO

TGF-β and RREB1 coordinate EMT programs in development and cancer

Project description:Epithelial-to-mesenchymal transitions (EMT) play prominent roles during development, regeneration and tumor progression. EMTs are triggered by TGF-β, RAS and other signals that cooperatively induce the expression of master EMT transcription factors such as SNAIL. Here, we elucidate how the TGF-β and RAS pathways jointly trigger EMTs and tie them to broader developmental programs. We identify RAS response element binding protein 1 (RREB1) as a critical partner of TGF-β-activated SMAD transcription factors in driving SNAIL expression in pancreatic pre-malignant epithelial cells, lung adenocarcinoma cells, and embryonic stem cells. Moreover, SMADs and RREB1 also drive EMT-associated fibrogenic programs in epithelial cells and mesendoderm differentiation in pluripotent embryonic cells. These findings illuminate the orchestration of EMT associated programs in gastrulation, fibrosis, and cancer.

2020-01-09 | GSE118765 | GEO

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