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

BMC Genomics
Martijn van HagenPernette J Verschure

Abstract

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. 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 numbe...Continue Reading

References

Aug 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·A ReinerA B Young
Mar 1, 1996·Annals of Neurology·M GuA H Schapira
Aug 6, 1999·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·C J CummingsH Y Zoghbi
Sep 29, 1999·Proceedings of the National Academy of Sciences of the United States of America·A KazantsevD Housman
May 18, 2000·Human Molecular Genetics·R Luthi-CarterJ M Olson
May 24, 2000·Proceedings of the National Academy of Sciences of the United States of America·J S SteffanL M Thompson
Jun 9, 2000·Annual Review of Neuroscience·H Y Zoghbi, H T Orr
Aug 25, 2000·Human Molecular Genetics·A McCampbellK H Fischbeck
Mar 29, 2001·Journal of Neuropathology and Experimental Neurology·E SappM DiFiglia
Nov 24, 2001·The Journal of Biological Chemistry·Raffaela PeroLorenzo Chiariotti
Feb 13, 2002·Molecular and Cellular Biology·Shi-Hua LiXiao-Jiang Li
Apr 25, 2002·Human Molecular Genetics·Zhao-Xue YuXiao-Jiang Li
Aug 13, 2002·The Journal of Biological Chemistry·Michelle A PoirierChristopher A Ross
Jul 15, 2003·Proceedings of the National Academy of Sciences of the United States of America·Kathryn M DonaldsonClaudio A P Joazeiro
Feb 13, 2004·Bioinformatics·Laurent GautierRafael A Irizarry
Jan 18, 2005·Nature Genetics·Jonathan CornettXiao-Jiang Li
May 7, 2005·Journal of Inherited Metabolic Disease·A A M Morris
Aug 23, 2005·Biological Psychiatry·Jane S PaulsenPeg C Nopoulos
Sep 24, 2005·BMC Bioinformatics·Ron ShamirRan Elkon
Sep 24, 2005·Annals of Neurology·M Flint Beal
Nov 8, 2005·Journal of Medical Genetics·L BertramR E Tanzi
Jan 13, 2006·Journal of Neurochemistry·Paula A DesplatsElizabeth A Thomas
Feb 2, 2006·BMC Molecular Biology·Andreas SchroederThomas Ragg
Feb 10, 2006·Human Molecular Genetics·Angela HodgesRuth Luthi-Carter
May 2, 2006·Statistical Applications in Genetics and Molecular Biology·Gordon K Smyth

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Citations

Jul 18, 2018·Molecular Medicine Reports·Xiaoyu Dong, Shuyan Cong
Jun 11, 2021·PloS One·Manuel Seefelder, Stefan Kochanek

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Methods Mentioned

BETA
chips
fluorescence microscopy

Software Mentioned

blast
arrayQualityMetrics
affy package
Bioconductor
biomaRt R /
Argos
Expander
Search Tool for the Retrieval of (
ComBat sva
limma

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