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

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

PROVIDER: PRJNA612330 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11297574_1.fastq.gz	Fastqsanger.gz
	SRR11297574_2.fastq.gz	Fastqsanger.gz
	SRR11297575_1.fastq.gz	Fastqsanger.gz
	SRR11297575_2.fastq.gz	Fastqsanger.gz
	SRR11297576_1.fastq.gz	Fastqsanger.gz

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

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

2020-03-13 | GSE146902 | GEO

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.

| PRJNA635794 | ENA

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

Compound craniosynostosis, intellectual disability and Noonan-like facial dysmorphism associated with 7q32.3-q35 deletion

Project description:Craniosynostosis (CS) is the premature fusion of the cranial sutures,occurring either in isolated or syndromic form. CS was described in over 180 genetic syndromes that comprise 15-30% of all CS cases. Syndromic CS usually has a monogenic inheritance and originates in most of the patients from mutations within the FGFR1, FGFR2, FGFR3, and TWIST1 genes. Causative alterations in other genes, or rarely copy number variations (CNVs) were also reported. In this paper, we describe a patient with Noonan-like facial dysmorphism accompanied by intellectual disability, and compound CS, involving coronal, sagittal, and squamous sutures. We have shown that the index carried a large and rare heterozygous deletion, which encompassed 12.782 Mb and mapped to a chromosomal region of 7q32.3-q35 (HG38 – chr7:131837067-144607071). The aberration comprised 109 protein-coding genes, including BRAF, that encodes serine/threonine-protein kinase B-Raf, being a part of the RAS/MAPK signaling pathway. The RAS/MAPK pathway plays an essential role in human development, hence its dysregulation not surprisingly results in severe congenital anomalies, such as phenotypically overlapping syndromes termed RASopathies. To our best knowledge, we report here the first CNV causing haploinsufficiency of BRAF, resulting in dysregulation of the RAS/MAPK cascade, and consequently, in the phenotype observed in our patient. To conclude, with this report, we have pointed to the involvement of the RAS/MAPK signaling pathway in CS development. Moreover, we have shown that the molecular analysis based on both DNA and RNA profiling, undoubtedly constitutes a comprehensive diagnostic and research strategy for elucidating a cause of genetic diseases.

2020-06-01 | GSE150754 | GEO

RNA-seq analysis of target genes in Noonan syndrome model mice with cardiac hypertrophy

Project description:Leucine-zipper-like transcriptional regulator 1 (LZTR1) is a member of the BTB-Kelch superfamily, which regulates the RAS proteostasis. Autosomal dominant (AD) mutations in LZTR1 have been identified in patients with Noonan syndrome (NS), a congenital anomaly syndrome. However, it remains unclear whether LZTR1 regulates the proteostasis of the RAS subfamily molecules and activate MAPK signaling pathway in heart. To investigate the impact of the LZTR1 mutant on gene expression, we performed RNA-seq analyses using LVs.

2024-10-23 | GSE254067 | 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

Intronic CRISPR repair in LZTR1-deficient iPSC-cardiomyocytes from Noonan syndrome patients reveals new treatment options

Project description:Noonan syndrome (NS) is a multisystemic developmental disorder characterized by its clinical variability with common symptoms such as typical facial dysmorphism, short stature, developmental delay and intellectual disability as well as congenital heart disease. The disease is causally linked to gain-of-function mutations in a number of genes leading to an increased signal transduction along the RAS-MAP kinase (MAPK) signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking. In this study, we present a family with two siblings displaying an autosomal recessive form of NS with severe hypertrophic cardiomyopathy caused by biallelic mutations within leucine zipper like transcription regulator 1 (LZTR1). Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of the affected siblings recapitulated the hypertrophic phenotype and uncovered a causal link between LZTR1 dysfunction, RAS accumulation, RAS-MAPK signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Intronic CRISPR repair in the patients’ iPSCs normalized RAS-MAPK signaling activity and cellular hypertrophy paving the way for personalized medical treatment.

2020-08-25 | PXD017530 | Pride

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

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