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Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations [RNA-seq]

ABSTRACT: Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations [RNA-seq]

PROVIDER: PRJNA484389 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7642080_1.fastq.gz	Fastqsanger.gz
	SRR7642080_2.fastq.gz	Fastqsanger.gz
	SRR7642090_1.fastq.gz	Fastqsanger.gz
	SRR7642090_2.fastq.gz	Fastqsanger.gz
	SRR7642081_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations

Project description:Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations

| PRJNA485183 | ENA

Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations [ChIP-seq]

Project description:Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations [ChIP-seq]

| PRJNA485186 | ENA

Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations [ChIP-seq]

Project description:We find that HTT binds ATF7IP, a regulator of the histone H3 methyltransferase SETDB1. HTT inhibits the interaction of the ATF7IP-SETDB1 complex with other heterochromatin regulators and transcriptional repressors, maintaining low levels of H3K9 trimethylation (H3K9me3) in hESCs. Conversely, loss of HTT promotes global increased H3K9me3 levels. To test whether HTT knockdown also induces enrichment of H3K9me3 marks at specific genes, we performed chromatin immunoprecipitation (ChIP)-sequencing assays of hESCs using an antibody to H3K9me3.

2018-09-04 | GSE118324 | GEO

Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations [RNA-seq]

2018-09-04 | GSE118088 | GEO

Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations

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

2018-09-04 | GSE118325 | GEO

Formation of toxic oligomers of polyQ-expanded Huntingtin by prion-mediated cross-seeding

Project description:Manifestation of aggregate pathology in Huntington’s disease is thought to be facilitated by a preferential vulnerability of affected brain cells to age-dependent proteostatic decline. To understand how specific cellular backgrounds may facilitate pathologic aggregation, we utilized the yeast model in which polyQ-expanded Huntingtin forms aggregates only when the endogenous prion-forming protein Rnq1 is in its amyloid-like prion [PIN+] conformation. We employed optogenetic clustering of polyQ protein as an orthogonal method to induce polyQ aggregation in prion-free [pin-] cells. Optogenetic aggregation circumvented the prion requirement for the formation of detergent-resistant polyQ inclusions, but bypassed the formation of toxic polyQ oligomers, which accumulated specifically in [PIN+] cells. Reconstitution of aggregation in vitro suggested that these polyQ oligomers formed through direct templating on Rnq1 prions. These findings shed light on the mechanism of prion-mediated formation of oligomers, which may play a role in triggering polyQ pathology in the patient brain.

2022-10-21 | PXD031337 | Pride

PolyQ-expansion does not alter the huntingtin-HAP40 complex

Project description:The amplification of a CAG repeat in the gene coding for huntingtin (HTT) leads to Huntington’s disease (HD). At the protein level, this translates into the expansion of a poly-glutamine (polyQ) stretch in the HTT N-terminus, which renders HTT aggregation-prone by unknown mechanisms. Here we investigate the effects of polyQ expansion on the HTT-HAP40 complex, where HTT structure is substantially stabilized. Surprisingly, our biophysical, cryo-EM and crosslinking mass spectrometry experiments reveal no major changes between 17QHTT-HAP40 (wild type), 46QHTT-HAP40 (typical polyQ length in HD patients) and 128QHTT-HAP40 (extreme polyQ length). Thus, the proposed destabilizing effect of HTT polyQ expansion may not suffice to alter the HTT-HAP40 complex, suggesting that polyQ expansion does not have a major global effect on HTT structure.

2021-03-19 | PXD018451 | Pride

Tadpole-like conformations of polyglutamine-expanded soluble huntingtin exon 1 engenders novel interactions

Project description:Soluble huntingtin exon 1 (Httex1) with expanded polyglutamine (polyQ) engenders neurotoxicity in Huntington’s disease. To understand the structural basis of this toxicity, we characterized the structure of monomeric Httex1 for two polyQ lengths using hydrogen-deuterium exchange and nuclear magnetic resonance experiments. NMR analysis of Httex1 with polyQ length of 25 glutamines showed the presence of helical structure in the N-terminal region which continued into the polyQ tract. Within these regions the 15N{1H} NOE averages about 0.4, consistent with a protein that lacks structure, but also consistent with Httex1 being not fully disordered. However, both NMR and mass spectrometry hydrogen-deuterium exchange experiments showed no protection suggesting a lack of any stabilizing hydrogen bonds. Atomistic simulations showed that these seemingly conflicting features originated from tadpole-like topologies composed of a globular head that included the N-terminal amphipathic region adsorbed on a collapsed polyQ domain and a semi-flexible C-terminal proline-rich region tail. The surface area of the disordered globular domain increased with polyQ length to promote gain-of-function interactions with a range of proteins in a mouse neuroblastoma cell model, which included the stress granule protein Fus. Overexpression of Fus potently reduced toxicity in cells with soluble, polyQ-expanded Httex1. These results collectively suggested that the tadpole-like structure of Httex1 stimulates novel gain-of-function interactions that can be harmful to cell viability and can be sequestered competitively by interactions with other proteins sharing similar low complexity structures such as Fus.

2019-11-08 | PXD006792 | Pride

Polyglutamine expanded huntingtin dramatically alters the genome-wide binding of HSF1 (mRNA)

Project description:In Huntington's disease (HD), polyglutamine expansions in the huntingtin (Htt) protein cause subtle changes in cellular functions that, over-time, lead to neurodegeneration and death. Studies have indicated that activation of the heat shock response can reduce many of the effects of mutant Htt in disease models, suggesting that the heat shock response is impaired in the disease. To understand the basis for this impairment, we have used genome-wide chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) to examine the effects of mutant Htt on the master regulator of the heat shock response, HSF1. We find that, under normal conditions, HSF1 function is highly similar in cells carrying either wild-type or mutant Htt. However, polyQ-expanded Htt severely blunts the HSF1-mediated stress response. Surprisingly, we find that the HSF1 targets most affected upon stress are not directly associated with proteostasis, but with cytoskeletal binding, focal adhesion and GTPase activity. Our data raise the intriguing hypothesis that the accumulated damage from life-long impairment in these stress responses may contribute significantly to the etiology of Huntington's disease. Affymetrix MG430 2.0 expression levels of wild-type (STHdhQ7/Q7) and mutant (STHdhQ111/Q111) striatal cells under growth condition (33 C) and upon heat shock (42 C for six hours)

2012-06-18 | E-GEOD-38001 | biostudies-arrayexpress

Polyglutamine expanded huntingtin dramatically alters the genome-wide binding of HSF1 (mRNA)

Project description:In Huntington’s disease (HD), polyglutamine expansions in the huntingtin (Htt) protein cause subtle changes in cellular functions that, over-time, lead to neurodegeneration and death. Studies have indicated that activation of the heat shock response can reduce many of the effects of mutant Htt in disease models, suggesting that the heat shock response is impaired in the disease. To understand the basis for this impairment, we have used genome-wide chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) to examine the effects of mutant Htt on the master regulator of the heat shock response, HSF1. We find that, under normal conditions, HSF1 function is highly similar in cells carrying either wild-type or mutant Htt. However, polyQ-expanded Htt severely blunts the HSF1-mediated stress response. Surprisingly, we find that the HSF1 targets most affected upon stress are not directly associated with proteostasis, but with cytoskeletal binding, focal adhesion and GTPase activity. Our data raise the intriguing hypothesis that the accumulated damage from life-long impairment in these stress responses may contribute significantly to the etiology of Huntington's disease.

2012-06-19 | GSE38001 | GEO

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