Identification of altered developmental pathways in human juvenile HD iPSC with 71Q and 109Q using transcriptome profiling
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ABSTRACT:
PROVIDER: PRJNA513014 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8393700_1.fastq.gz | Fastqsanger.gz | |||
| SRR8393700_2.fastq.gz | Fastqsanger.gz | |||
| SRR8393701_1.fastq.gz | Fastqsanger.gz | |||
| SRR8393701_2.fastq.gz | Fastqsanger.gz | |||
| SRR8393702_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: In Huntington disease (HD) subtle symptoms in patients may occur years or even decades prior to diagnosis. HD changes at a molecular level may begin as early as in cells that are non-lineage committed such as stem cells or HD patients induced pluripotent stem cells (iPSCs) offering opportunity to enhance the understanding of the HD pathogenesis. In addition, juvenile HD non-linage committed cells were previously not directly investigated in detail by RNA-seq. Methods: Strand-specific RNA-seq of the whole transcriptome was performed using 3 clonal lines from each of 2 HD patients (6 HD iPSC lines) with 71 or 109 CAG repeats in exon 1 of the HTT gene, and 2 healthy individuals, with 17/18 (2 clonal iPSC lines) and 21 CAG repeats (one iPSC line), to comprehensively identify mRNAs related to HD. A DESeq2 pipeline for transcripts of HD was developed to identify significantly dysregulated mRNAs. During the RNA-seq data analysis, we compared 6 HD iPSC lines vs control lines and also compared separately each set of 3 HD lines from one patient vs 3 control lines. As a result of such an approach, we generated statistical values for three comparison groups, HD vs WT, HD71Q vs WT and HD109Q vs WT Methods: 9 pM-indexed libraries were sequenced with the use of Illumina HiSeq2000, rapid run with paired-end 75 bp reads. On average, 65 mln reads were collected per library Results: We identified 107 (6 HD lines), 198 (3 HD71Q lines) and 217 (3 HD109Q lines) significantly dysregulated mRNAs in each comparison group. Conclusion: The analyses showed that many of dysregulated transcripts in HD109Q iPSC lines are involved in DNA damage response and apoptosis, such as CCND1, CDKN1A, TP53, BAX, TNFRSF10B, TNFRSF10C, TNFRSF10D, DDB2, PLCB1, PRKCQ, HSH2D, ZMAT3, PLK2, and RPS27L. Most of them were identified as downregulated and their proteins are direct interactors with TP53. HTT probably alters the level of several TP53 interactors influencing apoptosis.This may lead to accumulation of an excessive number of progenitor cells and potential disruption of cell differentiation and production of mature neurons. In addition, HTT effects on cell polarization also demonstrated in the analysis may result in a generation of incorrect progenitors.
2019-01-05 | GSE124664 | GEO
Project description:In Huntington disease (HD) subtle symptoms in patients may occur years or even decades prior to diagnosis. HD changes at a molecular level may begin as early as in cells that are non-lineage committed such as stem cells or HD patients induced pluripotent stem cells (iPSCs) offering opportunity to enhance the understanding of the HD pathogenesis. In addition, juvenile HD non-linage committed cells were previously not directly investigated in detail by RNA-seq. In the present manuscript, we define the early HD and juvenile HD transcriptional alterations using 6 human HD iPS cell lines from two patients, one with 71 CAGs and one with 109 CAG repeats. We identified 107 (6 HD lines), 198 (3 HD71Q lines) and 217 (3 HD109Q lines) significantly dysregulated mRNAs in each comparison group. The analyses showed that many of dysregulated transcripts in HD109Q iPSC lines are involved in DNA damage response and apoptosis, such as CCND1, CDKN1A, TP53, BAX, TNFRSF10B, TNFRSF10C, TNFRSF10D, DDB2, PLCB1, PRKCQ, HSH2D, ZMAT3, PLK2, and RPS27L. Most of them were identified as downregulated and their proteins are direct interactors with TP53. HTT probably alters the level of several TP53 interactors influencing apoptosis. This may lead to accumulation of an excessive number of progenitor cells and potential disruption of cell differentiation and production of mature neurons. In addition, HTT effects on cell polarization also demonstrated in the analysis may result in a generation of incorrect progenitors. Bioinformatics analysis of transcripts dysregulated in HD71Q iPSC lines showed that several of them act as transcription regulators during the early multicellular stages of development, such as ZFP57, PIWIL2, HIST1H3C, and HIST1H2BB. Significant upregulation of most of these transcripts may lead to a global increase in expression level of genes involved in pathways critical for embryogenesis and early neural development. In addition, MS analysis revealed altered levels of TP53 and ZFP30 proteins reflecting the functional significance of dysregulated mRNA levels of these proteins which were associated with apoptosis and DNA binding. Our finding very well corresponds to the fact that mutation in the HTT gene may cause precocious neurogenesis and identifies pathways likely disrupted during development.
| S-EPMC6345698 | biostudies-literature
Project description:Compared the global gene expression profiles of HD- and CON-iPSC-derived neurons We used microarrays to detail the global programme of gene expression for comparing the global gene expression profiles of HD- and CON-iPSC-derived neurons and facilitating studies of medium spiny neurons (MSN)-degenerative processes of Huntington's Disease (HD).
2015-09-02 | GSE59051 | GEO
Project description:Compared the global gene expression profiles of HD- and CON-iPSC-derived neurons We used microarrays to detail the global programme of gene expression for comparing the global gene expression profiles of HD- and CON-iPSC-derived neurons and facilitating studies of medium spiny neurons (MSN)-degenerative processes of Huntington's Disease (HD). By using a step-wise in vitro differentiation protocol combining EB formation, neural induction by small molecules, treatment with inhibitors of the TGFß pathway (SB431542) and the BMP pathway (LDN193189), and mechanical isolation/purification of neural progenitors and neurons, we induced 60-70% of control iPSCs or HD-iPSCs to differentiate into GABA- and DARPP-32- double positive neurons.
2015-09-02 | E-GEOD-59051 | biostudies-arrayexpress
Project description:Huntington's disease (HD) is a neurodegenerative disease caused by an expanded CAG repeat in the Huntingtin (HTT) gene. Induced pluripotent stem cell (iPSC) models of HD provide an opportunity to study the mechanisms underlying disease pathology in patient tissues relevant to disease. Murine studies have demonstrated that HTT is intricately involved in corticogenesis, and mutant (mt) HTT cannot compensate for the loss of non-CAG-expanded HTT. However, the critical effect of mtHTT in human corticogenesis has not yet been specifically explored and due to inherent differences in cortical development and timing between humans and mice. We therefore differentiated HD and non-diseased iPSCs into functional cortical neurons. While HD patient iPSCs can be successfully differentiated towards a cortical fate in culture, the resulting neurons display transcriptomic, morphological and functional phenotypes indicative of altered neurodevelopment. This is the first demonstration of altered corticogenesis from HD human patient cells, further supporting the potential neurodevelopmental aspect of HD.
2018-09-29 | GSE109534 | GEO
Project description:Huntington's disease (HD) is associated with dysfunction of the blood-brain barrier, including brain microvasscular endothelial cells (BMECs). We report changes in gene expression of induced pluripotent stem cells (iPSCs) and iPSC-derived brain microvascular endothelial cell-like cells (iBMECs) derived from an isogenic pair of iPSCs with either 180 (HD-corrected) or 18 (HD180) CAG repeats in the HTT gene.
2022-02-01 | GSE194416 | GEO
Project description:Purpose: The goals of this study are to compare the transcriptomic profile (mRNA-seq) of HD and control patient iPSC-derived neural cells to identify alterations in gene expression Methods: RNA were isolated from HD and control iPSC-derived neural cells. mRNAseq using Illumina Truseq mRNA PolyA+ v2 lib prep and Hiseq 2000. Statistical difference in mRNA levels were calculated with subsequent GO and pathway analysis Results: mRNAseq and statistical analysis revealed 1869 differentially expressed genes between HD and control iPSC-derived neural cells. Conclusions: Our study shows 1869 differentially expressed genes between HD and control iPSC-derived neural cells, and reveals gene networks that relevant to the mechanism of HD pathogenesis.
2017-03-20 | GSE95343 | GEO
Project description:Copy number variations (CNVs) at 7q11.23 cause Williams-Beuren (WBS) and 7q microduplication syndromes (7Dup), two neurodevelopmental disorders with shared and opposite cognitive-behavioral phenotypes. Using patient-derived and isogenic neurons, we integrated transcriptomics, translatomics and proteomics to elucidate the molecular underpinnings of this dosage effect. We found that 7q11.23 CNVs cause opposite alterations in neuronal differentiation and neuronal excitability. Here, the 7q11.23 CNV altered proteome in iPSC differentiating neurons was measured by a fast SWATH-MS method.
2024-10-17 | PXD038156 | Pride
Project description:Purpose: The goals of this study are to compare the transcriptomic profile (mRNA-seq) of HD and control patient iPSC-derived brain microvascular endotheial cells to identify alterations in gene expression. Methods: RNA were isolated from HD and control iPSC-derived brain microvascular endothelial cells. mRNAseq using Illumina TruSeq mRNA PolyA+ v2 lib prep and HiSeq 2500. Statistical difference in mRNA levels were calculated with subsequent GO and pathway analysis. Results: mRNAseq and statistical analysis revealed differentially expressed genes between HD and control iPSC-derived brain microvascular endothelial cells. Conclusions: Our study shows differentially expressed genes between HD and control iPSC-derived brain microvascular endothelial cells, and reveals gene networks that are relevant to the mechanism of HD pathogenesis.
2017-05-16 | GSE97100 | GEO