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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118324 | GEO | 2018/09/04

REPOSITORIES: GEO

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

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

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

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Amyloid modifier SERF1a interacts with polyQ-expanded huntingtin-exon 1 via helical interactions and exacerbates polyQ-induced toxicity.

Project description:Abnormal polyglutamine (polyQ) expansion and fibrillization occur in Huntington's disease (HD). Amyloid modifier SERF enhances amyloid formation, but the underlying mechanism is not revealed. Here, the fibrillization and toxicity effect of SERF1a on Htt-exon1 are examined. SERF1a enhances the fibrillization of and interacts with mutant thioredoxin (Trx)-fused Httex1. NMR studies with Htt peptides show that TrxHttex1-39Q interacts with the helical regions in SERF1a and SERF1a preferentially interacts with the N-terminal 17 residues of Htt. Time-course analysis shows that SERF1a induces mutant TrxHttex1 to a single conformation enriched of β-sheet. Co-expression of SERF1a and Httex1-polyQ in neuroblastoma and lentiviral infection of SERF1a in HD-induced polypotent stem cell (iPSC)-derived neurons demonstrates the detrimental effect of SERF1a in HD. Higher level of SERF1a transcript or protein is detected in HD iPSC, transgenic mice, and HD plasma. Overall, this study provides molecular mechanism for SERF1a and mutant Httex1 to facilitate therapeutic development for HD.

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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

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

Project description:In HuntingtonM-bM-^@M-^Ys 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. ChIP-Seq experiments for HSF-1 were performed in striatal cells that express either wild-type or mutant Htt using ChIP-Seq technology under normal (33M-BM-0C) and heat shock (42M-BM-0C for six hours) conditions. The cells were crosslinked with 1% formaldehyde and immunoprecipitated using antibody sc-9144 (Santa Cruz Biotech) for HSF-1. Sequencing was performed using the Illumina Genome Analyzer II.

2012-06-19 | E-GEOD-38000 | biostudies-arrayexpress

HAP40 orchestrates huntingtin structure for differential interaction with polyglutamine expanded exon 1

Project description:Huntington’s disease results from expansion of a glutamine-coding CAG tract in the huntingtin (HTT) gene, producing an aberrantly functioning form of HTT. Both wildtype and disease-state HTT form a hetero-dimer with HAP40 of unknown functional relevance. We demonstrate in vivo and in cell models that HTT and HAP40 cellular abundance are coupled. Integrating data from a 2.6 Å cryo-electron microscopy structure, cross-linking mass spectrometry, small-angle X-ray scattering, and modeling, we provide a near-atomic-level view of HTT, its molecular interaction surfaces and compacted domain architecture, orchestrated by HAP40. Native mass-spectrometry reveals a remarkably stable hetero-dimer, potentially explaining the cellular inter-dependence of HTT and HAP40. The exon 1 region of HTT is dynamic but shows greater conformational variety in the polyglutamine expanded mutant than wildtype exon 1. Our data provide a foundation for future functional and drug discovery studies targeting Huntington’s disease and illuminate the structural consequences of HTT polyglutamine expansion.

2022-09-09 | PXD028415 | Pride

HAP40 orchestrates huntingtin structure for differential interaction with polyglutamine expanded exon 1

2022-02-21 | PXD028313 | Pride