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SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome

ABSTRACT: SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome

PROVIDER: PRJNA718869 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11809821_1.fastq.gz	Fastqsanger.gz
	SRR11809821_2.fastq.gz	Fastqsanger.gz
	SRR11809822_1.fastq.gz	Fastqsanger.gz
	SRR11809822_2.fastq.gz	Fastqsanger.gz
	SRR11809823_1.fastq.gz	Fastqsanger.gz

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SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome.

Project description:The investigation of genetic forms of juvenile neurodegeneration could shed light on the causative mechanisms of neuronal loss. Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome caused by mutations in the SETBP1 gene, inducing the accumulation of its protein product. SGS features multi-organ involvement with severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here we introduce a human SGS model that displays disease-relevant phenotypes. We show that SGS neural progenitors exhibit aberrant proliferation, deregulation of oncogenes and suppressors, unresolved DNA damage, and resistance to apoptosis. Mechanistically, we demonstrate that high SETBP1 levels inhibit P53 function through the stabilization of SET, which in turn hinders P53 acetylation. We find that the inheritance of unresolved DNA damage in SGS neurons triggers the neurodegenerative process that can be alleviated either by PARP-1 inhibition or by NAD + supplementation. These results implicate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.

| S-EPMC8245514 | biostudies-literature

SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome

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

2021-06-03 | GSE171266 | GEO

SETBP1-WT and SETBP1-G870S transcriptional profiles [RNA-Seq]

Project description:RNA-Seq experiments on SETBP1-G870S and Empty cells was performed in order to assess if the presence of mutated SETBP1 may induce differential RNA expression.

2017-09-01 | GSE86333 | GEO

Transcriptional regulation by SETBP1 and SETBP1(D/N) in mouse hematopoietic stem and progenitor cells

Project description:Global gene expression changes induced by Setbp1 and Setbp1(D/N) in purified mouse hematopoietic stem and progenitor cells were characterized by RNA-seq analysis; ChIP-seq studies to identify cooperation between SETBP1/SETBP1(D/N) and MLL1 in regulating gene transcription in hematopoietic stem and progenitor cells.

2021-12-17 | GSE167301 | GEO

SETBP1-WT and SETBP1-G870S epigenetic landscapes [ChIP-Seq]

Project description:ChIP-Seq experiments targeting H3K4me2, H3K4me3, H3K9ac, H3K27ac, H3K36me3 histone modifications have been performed in order to assess if SETBP1 binding to gDNA was associated with chromatin remodeling and to further characterize the mechanisms responsible for SETBP1-mediated transcriptional regulation

2017-09-01 | GSE86328 | GEO

SETBP1-WT and SETBP1-G870S epigenetic landscapes

Project description:SETBP1-WT and SETBP1-G870S epigenetic landscapes

| PRJNA341463 | ENA

p53 prevents neurodegeneration by regulating synaptic genes

Project description:DNA damage has been implicated in neurodegenerative disorders, including Alzheimer’s disease and other tauopathies, but the consequences of genotoxic stress to postmitotic neurons are poorly understood. Here we demonstrate that p53, a key mediator of the DNA damage response, plays a neuroprotective role in a Drosophila model of tauopathy. Further, through a whole-genome ChIP-chip analysis we identify genes controlled by p53 in postmitotic neurons. We genetically validate a specific pathway, synaptic function, in p53-mediated neuroprotection. We then demonstrate that the control of synaptic genes by p53 is conserved in mammals. Collectively, our results implicate synaptic function as a central target in p53-dependent protection from neurodegeneration. 4 samples: tau vs. control

2015-01-06 | E-GEOD-40418 | biostudies-arrayexpress

SETBP1-WT and SETBP1-G870S DNA binding propensity [ChIP-Seq TF]

Project description:ChIP-seq against V5 has been performed in order to investigate the role of SETBP1 as a DNA binding protein

2017-09-01 | GSE86334 | GEO

p53 prevents neurodegeneration by regulating synaptic genes

2015-01-06 | GSE40418 | GEO

Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms

Project description:Colony stimulating factor 3 receptor (CSF3R) mutations lead to JAK pathway activation and are the molecular hallmark of chronic neutrophilic leukemia (CNL). Approximately half of CNL patients also have mutations in SET binding protein 1 (SETBP1). In this study, we developed models of SETBP1-mutant leukemia to understand the role that SETBP1 plays in CNL. SETBP1 mutations promote self-renewal of CSF3R-mutant hematopoietic progenitors in vitro and prevent cells from undergoing terminal differentiation. In vivo, SETBP1 mutations accelerate leukemia progression, leading to the rapid development of hepatosplenomegaly and granulocytosis. Through transcriptomic and epigenomic profiling, we found that SETBP1 enhances progenitor-associated programs—most strongly upregulating Myc and Myc target genes. In summary, we find that SETBP1 mutations promote aggressive hematopoietic cell expansion when expressed with mutant CSF3R through the upregulation of Myc-associated gene expression programs.

2022-05-11 | GSE189502 | GEO

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