ArticleBMC genomics2017
The dynamics of early-state transcriptional changes and aggregate formation in a Huntington's disease cell model.
Article in BMC genomics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 2 of them syntheses that pooled it.
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Who cites it
16 citing papers in PubMed, 2 syntheses or guidelines pooled it, 26 citations in OpenAlex.
- Pooled it
- The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.Pharmacology & therapeutics · 2020Pooled it
- Autophagy activator AA-20 improves proteostasis and extendsProceedings of the National Academy of Sciences of the United States of America · 2025Article
- The role(s) of NF-Y in development and differentiation.Cell death and differentiation · 2025Review
- Identification of molecular targets and small drug candidates for Huntington's disease via bioinformatics and a network-based screening approach.Journal of cellular and molecular medicine · 2024Article
- A Comprehensive Bioinformatics Approach to Identify Molecular Signatures and Key Pathways for the Huntington Disease.Bioinformatics and biology insights · 2023Article
- HSF1, Aging, and Neurodegeneration.Advances in experimental medicine and biology · 2023Review
- Nrf2 Pathway in Huntington's Disease (HD): What Is Its Role?International journal of molecular sciences · 2022Review
- Esculetin Provides Neuroprotection against Mutant Huntingtin-Induced Toxicity in Huntington's Disease Models.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Osmolytes dynamically regulate mutant Huntingtin aggregation and CREB function in Huntington's disease cell models.Scientific reports · 2020Article
- Gedunin Degrades Aggregates of Mutant Huntingtin Protein and Intranuclear Inclusions via the Proteasomal Pathway in Neurons and Fibroblasts from Patients with Huntington's Disease.Neuroscience bulletin · 2019Article
- Chromatin accessibility and transcription dynamics during in vitro astrocyte differentiation of Huntington's Disease Monkey pluripotent stem cells.Epigenetics & chromatin · 2019Article
- Heat shock promotes inclusion body formation of mutant huntingtin (mHtt) and alleviates mHtt-induced transcription factor dysfunction.The Journal of biological chemistry · 2018Article
- Mutant Huntingtin Causes a Selective Decrease in the Expression of Synaptic Vesicle Protein 2C.Neuroscience bulletin · 2018Article
- Bioinformatic analysis of microRNA expression in Huntington's disease.Molecular medicine reports · 2018Article
- Huntington's disease: the coming of age.Journal of genetics · 2018Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHuntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene. Proteolytic cleavage of mutant huntingtin (Htt) protein with an expanded polyglutamine (polyQ) stretch results in production of Htt fragments that aggregate and induce impaired ubiquitin proteasome, mitochondrial functioning and transcriptional dysregulation. To understand the time-resolved relationship between aggregate formation and transcriptional changes at early disease stages, we performed temporal transcriptome profiling and quantification of aggregate formation in living cells in an inducible HD cell model.
resultsRat pheochromocytoma (PC12) cells containing a stably integrated, doxycycline-inducible, eGFP-tagged N-terminal human Htt fragment with an expanded polyQ domain were used to analyse gene expression changes at different stages of mutant Htt aggregation. At earliest time points after doxycycline induction no detectable aggregates and few changes in gene expression were observed. Aggregates started to appear at intermediate time points. Aggregate formation and subsequent enlargement of aggregates coincided with a rapid increase in the number of differentially expressed (DE) genes. The increase in number of large aggregates coincided with a decrease in the number of smaller aggregates whereas the transcription profile reverted towards the profile observed before mutant Htt induction. Cluster-based analysis of the 2,176 differentially expressed genes revealed fourteen distinct clusters responding differently over time. Functional enrichment analysis of the two major gene clusters revealed that genes in the up-regulated cluster were mainly involved in metabolic (antioxidant activity and cellular ketone metabolic processes) and genes in the down-regulated cluster in developmental processes, respectively. Promoter-based analysis of the identified gene clusters resulted in identification of a transcription factor network of which several previously have been linked to HD.
conclusionsWe demonstrate a time-resolved relationship between Htt aggregation and changes in the transcriptional profile. We identified two major gene clusters showing involvement of (i) mitochondrial dysfunction and (ii) developmental processes implying cellular homeostasis defects. We identified novel and known HD-linked transcription factors and show their interaction with known and predicted regulatory proteins. Our data provide a novel resource for hypothesis building on the role of transcriptional key regulators in early stages of HD and possibly other polyQ-dependent diseases.
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