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Expression analysis in yeast model of Huntington's disease (HD)

ABSTRACT: Expressing a mutant fragment of huntingtin (Htt) in yeast produces several HD-relevant phenotypes. We used microarrays to study global change in expression induced by this mutant htt fragment. Expression was also analysed in three suppressor deletion strains expressing a toxic mutant htt fragment: bna4Δ, mbf1Δ, and ume1Δ. Yeast samples expressing either a wild-type or mutant htt fragment (Htt25Q or Htt103Q, respectively), and suppressor deletion strains expressing Htt103Q: bna4Δ, mbf1Δ, and ume1Δ.

ORGANISM(S): Saccharomyces cerevisiae

SUBMITTER: Eran Tauber

PROVIDER: E-GEOD-18644 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Functional gene expression profiling in yeast implicates translational dysfunction in mutant huntingtin toxicity.

Tauber Eran E Miller-Fleming Leonor L Mason Robert P RP Kwan Wanda W Clapp Jannine J Butler Nicola J NJ Outeiro Tiago F TF Muchowski Paul J PJ Giorgini Flaviano F

The Journal of biological chemistry 20101102 1

Huntington disease (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine tract in the huntingtin (htt) protein. To uncover candidate therapeutic targets and networks involved in pathogenesis, we integrated gene expression profiling and functional genetic screening to identify genes critical for mutant htt toxicity in yeast. Using mRNA profiling, we have identified genes differentially expressed in wild-type yeast in response to mutant htt toxicity as well as in three to ...[more]

PMID: 21044956

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Expression analysis in yeast model of Huntington's disease (HD)

Project description:Expressing a mutant fragment of huntingtin (Htt) in yeast produces several HD-relevant phenotypes. We used microarrays to study global change in expression induced by this mutant htt fragment. Expression was also analysed in three suppressor deletion strains expressing a toxic mutant htt fragment: bna4Δ, mbf1Δ, and ume1Δ.

2010-11-09 | GSE18644 | GEO

Htt-N171 HD in vitro

Project description:4 Treatment groups: A) Uninfected B) Infected 6 weeks prior with GFP-expressing recombinant lentivirus C) Infected 6 weeks prior with Htt-N171-19Q-expressing recombinant lentivirus D)Infected 6 weeks prior with Htt-N171-82Q-expressing recombinant lentivirus Keywords = huntington Keywords: parallel sample

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Expression data of hypothalamus from the BACHD and HTT overexpression mouse models of Huntington's disease (HD)

Project description:We used microarrays to investigate whether transcriptional dysregulation in hypothalamus is caused by expression of the huntingtin (HTT) protein We used two different Huntington's disease mouse models: BACHD mice with ubiquitous full-length mutant HTT expression (97 CAG repeats) and wild-type mice with targeted bilateral injections of wild-type or mutant HTT (853 amino acids length, wild-type HTT: 18 CAG repeats, mutant HTT: 79 CAG repeats) in hypothalamus.

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Reduced Representation Bisulfite Sequencing from HD knock-in mouse model

Project description:We generated two types of DNA methylation datasets (Reduced Representation Bisulfite Sequencing [RRBS] and custom methylation array) from a heterozygous HD knock-in mouse model. The heterozygous Htt knock-in line expressed one wildtype endogenous Htt allele and a second Htt allele with knock-in of human mHTT exon 1 with either approximately 190 CAG repeats (Q175) or 20 CAG repeats (Q20). For each genotype (Q175 and Q20) we analyzed two brain regions (striatum and cerebellum) from 8 mice each on the RRBS platform (N=32 RRBS samples). Our EWAS of mutant Htt gene status (i.e. Q175 status) across the two brain regions identified two genome-wide significant CpGs in Htt region. contributor: CHDI foundation

2020-07-02 | GSE147156 | GEO

SUMO-targeted ubiquitin ligases (STUbLs) reduce the toxicity and abnormal transcriptional activity associated with a mutant, aggregation-prone fragment of huntingtin

Project description:We report that the SUMO-targeted ubiquitin ligase (STUbL) Slx5 reduces the toxicity and abnormal transcriptional activity of a mutant, aggregation-prone fragment of huntingtin (htt), the causative agent of HD. An extra copy of SLX5 specifically reduces htt aggregates in the cytosol as well as chromatin-associated htt aggregates in the nucleus. Using RNA sequencing, we identified and confirmed specific targets of mHtt's transcriptional activity that are modulated by Slx5.

2018-06-20 | GSE115990 | GEO

Gene expression analysis in the presence or absence of N-terminal tag (9myc) of Swd2 in Saccharomyces cerevisiae

Project description:project abstract : H3K4 methylation is a well-conserved histone modification from yeast to human. Because H3K4 methylase Set1 and its complex, COMPASS (Complex of proteins associated with Set1), are conserved from yeast to humans, budding yeast has been studied as an acceptable model organism. Since COMPASS components affect Set1 protein stability and H3K4 methylation activity variously, it is important to study how Set1 is regulated by complex components. However, deletion mutant of Swd2 component of COMPASS is not viable, although overexpression of Sen1 fragment enables the construction of Swd2 deletion mutant. This study found that positioning epitope tag to the N-terminal of Swd2 did not decrease interaction between Swd2 and Set1, but reduced the stability of both proteins, Swd2 and Set1, and global H3K4 methylation. Also, we observed that overexpression of N-terminal tagged Swd2 caused increased Set1 protein level and bulk H3K4 methylation. Therefore, Set1 protein can maintain its protein level only when enough Swd2 exist to cover the protein amount of Set1. Also, by comparing RNA sequencing analysis of N-terminal tagged Swd2 and Swd2 deletion mutant with Sen1 fragment overexpression, we isolated genes regulated by Swd2. In conclusion, we suggest that the abundance of Swd2 is important to regulate the protein stability of Set1 and the regulation of gene expression.

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Specificity assessment of allele selective Zinc Finger Protein Repressors in HD fibroblasts

Project description:Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin gene (HTT), which codes for the pathologic mutant HTT (mHTT) protein. Since normal HTT is thought to be important for brain function, we engineered zinc finger protein transcription factors (ZFP-TFs) to target the pathogenic CAG repeat and selectively lower mHTT as a therapeutic strategy. Using patient-derived fibroblasts and neurons, we demonstrate that ZFP-TFs selectively repress >99% of HD-causing alleles over a wide dose range, while preserving expression of >86% of normal alleles. Other CAG-containing genes are minimally affected, and virally delivered ZFP-TFs are active and well tolerated in HD neurons beyond 100 days in culture and at least 9 months in the mouse brain. Using three HD mouse models, we demonstrate improvements in a range of molecular, histopathological, electrophysiological, and functional endpoints. Our findings support the continued development of an allele-selective ZFP-TF for the treatment of HD.

2019-06-30 | GSE127820 | GEO

Saccharomyces cerevisiae

Project description:Yeast heterozygous FHL1 deletion mutant

| PRJNA377576 | ENA

Specificity assessment of allele selective Zinc Finger Protein Repressors in hESC-derived HD neurons

2019-06-30 | GSE127821 | GEO

Global genomic mapping, in Saccharomyces cerevisiae, of new suppressor alleles of the RNA polymerase I subunit rpa49 deletion.

Project description:In the yeast saccharoryces cerevisiae, RPA49 full-deletion mutants show a strong growth defect at 30°C and are unable to grow at 25°C. However, spontaneous suppressors that restore growth at 25°C are observed. We attend to identified new suppressor alleles after UV treatment. To mapped the genomic location of suppressor allele we have used a derivative of the so called \\"Genetic Interaction Mapping\\" (GIM) method (Decourty et al, 2008). Briefly, we have mated a yeast strain carrying the deletion of rpa49 and the a suppressor allele (query strain) with the pool of all haploid deletion mutants from the Euroscarf yeast gene deletion project. All deletions in strains from the Euroscarf collection are flanked by 2 unique 20 bases pair DNA tag (so-called Up-Tag and DN-tag) that allow detection on oligonucleotide micro-array. After sporulation in mass, spores carrying the rpa49 deletion, the suppressor allele and euroscarf deleted genes were selected and grow in a competition culture for 10 generations. As selected spores result from genetic re-association of allele from tested strains and euroscarf strain, all strains carrying a deleted genes from the euroscarf collection that is genetically link to the suppressor allele will be depleted in the culture. We next extract genomic DNA , amplified and labelled the tags. The relative quantity of each deletion tags in experiments with strain carrying suppressor alleles were estimated in a two color array experiment relative to the quantity of the tags in parallel experiments using two different wild-type strains.

2019-12-31 | E-MTAB-7831 | biostudies-arrayexpress

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