Intersecting impact of CAG repeat and Huntingtin knockout in stem cell-derived cortical neurons [cortical]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1189496 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31444000_1.fastq.gz | Fastqsanger.gz | |||
| SRR31444000_2.fastq.gz | Fastqsanger.gz | |||
| SRR31444001_1.fastq.gz | Fastqsanger.gz | |||
| SRR31444001_2.fastq.gz | Fastqsanger.gz | |||
| SRR31444002_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 150 |
Similar Datasets
Project description:Huntington’s Disease (HD) is caused by a CAG repeat expansion in the gene encoding Huntingtin (HTT). While normal HTT function appears impacted by the mutation, the specific pathways unique to CAG repeat expansion versus loss of normal function are unclear. To understand the impact of the CAG repeat expansion, we evaluated biological signatures of HTT knockout (HTT KO) versus those that occur from the CAG repeat expansion by applying multi-omics, live cell imaging, survival analysis and a novel feature- based pipeline to study cortical neurons (eCNs) derived from an isogenic human embryonic stem cell series (RUES2). HTT KO and the CAG repeat expansion influence developmental trajectories of eCNs, with opposing effects on the growth. Network analyses of differentially expressed genes and proteins associated with enriched epigenetic motifs identified subnetworks common to CAG repeat expansion and HTT KO that include neuronal differentiation, cell cycle regulation, and mechanisms related to transcriptional repression and may represent gain-of-function mechanisms that cannot be explained by HTT loss of function alone. A combination of dominant and loss-of-function mechanisms are likely involved in the aberrant neurodevelopmental and neurodegenerative features of HD that can help inform therapeutic strategies.
2025-05-05 | GSE282626 | GEO
Project description:Huntington’s Disease (HD) is caused by a CAG repeat expansion in the gene encoding Huntingtin (HTT). While normal HTT function appears impacted by the mutation, the specific pathways unique to CAG repeat expansion versus loss of normal function are unclear. To understand the impact of the CAG repeat expansion, we evaluated biological signatures of HTT knockout (HTT KO) versus those that occur from the CAG repeat expansion by applying multi-omics, live cell imaging, survival analysis and a novel feature- based pipeline to study cortical neurons (eCNs) derived from an isogenic human embryonic stem cell series (RUES2). HTT KO and the CAG repeat expansion influence developmental trajectories of eCNs, with opposing effects on the growth. Network analyses of differentially expressed genes and proteins associated with enriched epigenetic motifs identified subnetworks common to CAG repeat expansion and HTT KO that include neuronal differentiation, cell cycle regulation, and mechanisms related to transcriptional repression and may represent gain-of-function mechanisms that cannot be explained by HTT loss of function alone. A combination of dominant and loss-of-function mechanisms are likely involved in the aberrant neurodevelopmental and neurodegenerative features of HD that can help inform therapeutic strategies.
2025-04-29 | GSE284565 | GEO
Project description:Huntington’s Disease (HD) is caused by a CAG repeat expansion in the gene encoding Huntingtin (HTT). While normal HTT function appears impacted by the mutation, the specific pathways unique to CAG repeat expansion versus loss of normal function are unclear. To understand the impact of the CAG repeat expansion, we evaluated biological signatures of HTT knockout (HTT KO) versus those that occur from the CAG repeat expansion by applying multi-omics, live cell imaging, survival analysis and a novel feature- based pipeline to study cortical neurons (eCNs) derived from an isogenic human embryonic stem cell series (RUES2). HTT KO and the CAG repeat expansion influence developmental trajectories of eCNs, with opposing effects on the growth. Network analyses of differentially expressed genes and proteins associated with enriched epigenetic motifs identified subnetworks common to CAG repeat expansion and HTT KO that include neuronal differentiation, cell cycle regulation, and mechanisms related to transcriptional repression and may represent gain-of-function mechanisms that cannot be explained by HTT loss of function alone. A combination of dominant and loss-of-function mechanisms are likely involved in the aberrant neurodevelopmental and neurodegenerative features of HD that can help inform therapeutic strategies.
2025-05-05 | GSE282628 | GEO
Project description:Huntington’s Disease (HD) is caused by a CAG repeat expansion in the gene encoding Huntingtin (HTT). While normal HTT function appears impacted by the mutation, the specific pathways unique to CAG repeat expansion versus loss of normal function are unclear. To understand the impact of the CAG repeat expansion, we evaluated biological signatures of HTT knockout (HTT KO) versus those that occur from the CAG repeat expansion by applying multi-omics, live cell imaging, survival analysis and a novel feature- based pipeline to study cortical neurons (eCNs) derived from an isogenic human embryonic stem cell series (RUES2). HTT KO and the CAG repeat expansion influence developmental trajectories of eCNs, with opposing effects on the growth. Network analyses of differentially expressed genes and proteins associated with enriched epigenetic motifs identified subnetworks common to CAG repeat expansion and HTT KO that include neuronal differentiation, cell cycle regulation, and mechanisms related to transcriptional repression and may represent gain-of-function mechanisms that cannot be explained by HTT loss of function alone. A combination of dominant and loss-of-function mechanisms are likely involved in the aberrant neurodevelopmental and neurodegenerative features of HD that can help inform therapeutic strategies.
2025-04-29 | GSE284798 | GEO
Project description:Intersecting impact of CAG repeat and Huntingtin knockout in stem cell-derived cortical neurons
| PRJNA1199548 | ENA
Project description:Intersecting impact of CAG repeat and Huntingtin knockout in stem cell-derived cortical neurons [cortical_bulkRNASeq]
| PRJNA1200684 | ENA
Project description:Intersecting impact of CAG repeat and Huntingtin knockout in stem cell-derived cortical neurons [ESC]
| PRJNA1189503 | ENA
Project description:To gain insight into how mutant Huntingtin (mHTT) CAG repeat length may modify Huntington’s disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat length. We find repeat length dependent transcriptional signatures are prominent in the striatum, less so in cortex, and minimal in the liver. Co-expression network analyses reveal 13 striatal and 5 cortical modules that are highly correlated with CAG length and age, and that are preserved in HD models and some in the patients. Top striatal modules implicate mHTT CAG length and age in graded impairment of striatal medium spiny neuron identity gene expression and in dysregulation of cAMP signaling, cell death, and protocadherin genes. Importantly, we used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at both RNA and protein levels and validated 21 striatal module genes as modifiers of mHtt toxicities in vivo.
2016-02-16 | PXD003442 | Pride
Project description:In Huntington’s disease (HD), expanded HTT CAG repeat length correlates strongly with age at motor onset, indicating that it determines the rate of the disease process leading to diagnostic clinical manifestations. Similarly, in normal individuals, HTT CAG repeat length is correlated with biochemical differences that reveal it as a functional polymorphism. Here, we tested the hypothesis that gene expression signatures can capture continuous, length-dependent effects of the HTT CAG repeat. Using gene expression datasets for 107 HD and control lymphoblastoid cell lines, we constructed mathematical models in an iterative manner, based upon CAG correlated gene expression patterns in randomly chosen training samples, and tested their predictive power in test samples. Predicted CAG repeat lengths were significantly correlated with experimentally determined CAG repeat lengths, whereas models based upon randomly permuted CAGs were not at all predictive. Predictions from different batches of mRNA for the same cell lines were significantly correlated, implying that CAG length-correlated gene expression is reproducible. Notably, HTT expression was not itself correlated with HTT CAG repeat length. Taken together, these findings confirm the concept of a gene expression signature representing the continuous effect of HTT CAG length and not primarily dependent on the level of huntingtin expression. Such global and unbiased approaches, applied to additional cell types and tissues, may facilitate the discovery of therapies for HD by providing a comprehensive view of molecular changes triggered by HTT CAG repeat length for use in screening for and testing compounds that reverse effects of the HTT CAG expansion. To evaluate the continuous analytical approach as a strategy to discover the molecular consequences of the HTT CAG repeat, genome-wide gene expression datasets were generated from a panel of 107 human lymphoblastoid cell lines with HTT CAGs spanning the entire spectrum of allele sizes.
2013-05-03 | E-GEOD-34721 | biostudies-arrayexpress
Project description:Huntington’s disease (HD) is caused by CAG repeat expansion at the N-terminal region of huntingtin (HTT) gene and characterize by neuronal cell loss and neuroinflammation transcriptional profile change in striatum, cortex and other brain regions. Here we reported generation and characterization of BAC-CAG, a novel full length human HD mouse model host over 120 uninterrupted CAG repeats. we performed RNA-seq analysis of the striatum and cortex of BAC-CAG mice at 2m, 6m and 12m of age (N=6 per genotype, sex balanced). We observed an age-dependent transcriptionopathy in the striatum of BAC-CAG mice, with only 7 and 36 significant DE genes in 2m and 6m striatum respectively (FDR<0.1), but 820 DE genes (538 downregulated and 282 upregulated genes) at 12m of age (FDR<0.1). The transcriptomic deficits in this model are highly striatum-selective, as we only detected 4, 3 and 14 DE genes (FDR<0.1) at 2m, 6m and 12m respectively in BAC-CAG cortices compared to WT controls. Remarkably, we found a highly significant positive transcriptome-wide correlation (r=0.62) of DE Z statistics between BAC-CAG vs WT at 12m and Q140 vs WT at 6m (p<1e-200). This result demonstrates a high concordance of both upregulated and downregulated genes in the BAC-CAG striatum compared to that of allelic series KI mice; but RNA-seq studies of BACHD mice at 12m and found only 50 genes significantly differentially expressed (DE) genes (FDR<0.1) in the striatum at 12m of age compared to WT littermates, 31 downregulated and 19 upregulated genes. In the cortex at 12m of age, BACHD only showed 6 significantly downregulated genes and 7 upregulated genes comapred to WT controls (FDR<0.1).
2022-02-02 | GSE153827 | GEO