دورية أكاديمية
أعرض في EDS

The dynamics of early-state transcriptional changes and aggregate formation in a Huntington's disease cell model.

التفاصيل البيبلوغرافية
العنوان: The dynamics of early-state transcriptional changes and aggregate formation in a Huntington's disease cell model.
المؤلفون: van Hagen M; Synthetic, Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.; Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands., Piebes DGE; Synthetic, Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands., de Leeuw WC; MicroArray Department, University of Amsterdam, Amsterdam, The Netherlands., Vuist IM; Synthetic, Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands., van Roon-Mom WMC; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands., Moerland PD; Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands., Verschure PJ; Synthetic, Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands. P.J.Verschure@uva.nl.
المصدر: BMC genomics [BMC Genomics] 2017 May 12; Vol. 18 (1), pp. 373. Date of Electronic Publication: 2017 May 12.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 100965258 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2164 (Electronic) Linking ISSN: 14712164 NLM ISO Abbreviation: BMC Genomics Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : BioMed Central, [2000-
مواضيع طبية MeSH: Gene Expression Profiling* , Protein Aggregates* , Transcription, Genetic*, Huntingtin Protein/*chemistry , Huntingtin Protein/*genetics , Huntington Disease/*pathology, Animals ; Humans ; Huntington Disease/genetics ; Multigene Family/genetics ; Mutation ; PC12 Cells ; Promoter Regions, Genetic/genetics ; Rats ; Transcription Factors/metabolism
مستخلص: Background: Huntington'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.
Results: Rat 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.
Conclusions: We 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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فهرسة مساهمة: Keywords: Aggregates; Early HD cellular phenotype; Gene clusters; Huntington's disease; Inducible HD cell line; Temporal analysis; Transcription
المشرفين على المادة: 0 (Huntingtin Protein)
0 (Protein Aggregates)
0 (Transcription Factors)
تواريخ الأحداث: Date Created: 20170514 Date Completed: 20171225 Latest Revision: 20181113
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC5429582
DOI: 10.1186/s12864-017-3745-z
PMID: 28499347
قاعدة البيانات: MEDLINE
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