Repressor element-1 silencing transcription factor (REST) is present in human control and Huntington's disease neurones

2014 ◽  
Vol 40 (7) ◽  
pp. 899-910 ◽  
Author(s):  
Davide Schiffer ◽  
Valentina Caldera ◽  
Marta Mellai ◽  
Paola Conforti ◽  
Elena Cattaneo ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Human Control ◽  
Repressor Element

scholarly journals Osmolytes dynamically regulate mutant Huntingtin aggregation and CREB function in Huntington’s disease cell models

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Shreyaas Aravindan ◽  
Samantha Chen ◽  
Hannaan Choudhry ◽  
Celine Molfetta ◽  
Kuang Yu Chen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Inclusion Bodies ◽  
Cell Model ◽  
Mutant Huntingtin ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Disease Protein ◽  
Disease Cell

Abstract Osmolytes are organic solutes that change the protein folding landscape shifting the equilibrium towards the folded state. Herein, we use osmolytes to probe the structuring and aggregation of the intrinsically disordered mutant Huntingtin (mHtt) vis-a-vis the pathogenicity of mHtt on transcription factor function and cell survival. Using an inducible PC12 cell model of Huntington’s disease (HD), we show that stabilizing polyol osmolytes drive the aggregation of Htt103QExon1-EGFP from a diffuse ensemble into inclusion bodies (IBs), whereas the destabilizing osmolyte urea does not. This effect of stabilizing osmolytes is innate, generic, countered by urea, and unaffected by HSP70 and HSC70 knockdown. A qualitatively similar result of osmolyte-induced mHtt IB formation is observed in a conditionally immortalized striatal neuron model of HD, and IB formation correlates with improved survival under stress. Increased expression of diffuse mHtt sequesters the CREB transcription factor to repress CREB-reporter gene activity. This repression is mitigated either by stabilizing osmolytes, which deplete diffuse mHtt or by urea, which negates protein–protein interaction. Our results show that stabilizing polyol osmolytes promote mHtt aggregation, alleviate CREB dysfunction, and promote survival under stress to support the hypothesis that lower molecular weight entities of disease protein are relevant pathogenic species in neurodegeneration.

scholarly journals Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s disease

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Rocio Gomez-Pastor ◽  
Eileen T. Burchfiel ◽  
Daniel W. Neef ◽  
Alex M. Jaeger ◽  
Elisa Cabiscol ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Stress

scholarly journals Control of Huntington’s Disease-Associated Phenotypes by the Striatum-Enriched Transcription Factor Foxp2

Cell Reports ◽  
2017 ◽  
Vol 21 (10) ◽  
pp. 2688-2695 ◽  
Author(s):  
Lea J. Hachigian ◽  
Vitor Carmona ◽  
Robert J. Fenster ◽  
Ruth Kulicke ◽  
Adrian Heilbut ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Huntington's Disease ◽  
Huntington’S Disease

Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease

2006 ◽  
Vol 22 (2) ◽  
pp. 233-241 ◽  
Author(s):  
Alice S. Chen-Plotkin ◽  
Ghazaleh Sadri-Vakili ◽  
George J. Yohrling ◽  
Melissa W. Braveman ◽  
Caroline L. Benn ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Transcription Factor Sp1

scholarly journals Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in Huntington’s disease

2019 ◽  
Vol 116 (49) ◽  
pp. 24840-24851 ◽  
Author(s):  
Ferah Yildirim ◽  
Christopher W. Ng ◽  
Vincent Kappes ◽  
Tobias Ehrenberger ◽  
Siobhan K. Rigby ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Beneficial Effects ◽  
Transcriptional Dysregulation ◽  
Clinical Onset ◽  
Transcriptional Changes ◽  
Chromatin Profiling

Huntington’s disease (HD) is a chronic neurodegenerative disorder characterized by a late clinical onset despite ubiquitous expression of the mutant Huntingtin gene (HTT) from birth. Transcriptional dysregulation is a pivotal feature of HD. Yet, the genes that are altered in the prodromal period and their regulators, which present opportunities for therapeutic intervention, remain to be elucidated. Using transcriptional and chromatin profiling, we found aberrant transcription and changes in histone H3K27acetylation in the striatum of R6/1 mice during the presymptomatic disease stages. Integrating these data, we identified the Elk-1 transcription factor as a candidate regulator of prodromal changes in HD. Exogenous expression of Elk-1 exerted beneficial effects in a primary striatal cell culture model of HD, and adeno-associated virus-mediated Elk-1 overexpression alleviated transcriptional dysregulation in R6/1 mice. Collectively, our work demonstrates that aberrant gene expression precedes overt disease onset in HD, identifies the Elk-1 transcription factor as a key regulator linked to early epigenetic and transcriptional changes in HD, and presents evidence for Elk-1 as a target for alleviating molecular pathology in HD.

Transcriptional dysregulation of coding and non-coding genes in cellular models of Huntington's disease

2009 ◽  
Vol 37 (6) ◽  
pp. 1270-1275 ◽  
Author(s):  
Angela Bithell ◽  
Rory Johnson ◽  
Noel J. Buckley
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Target Genes ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Cag Repeat ◽  
Contributory Factor ◽  
Cellular Models

HD (Huntington's disease) is a late onset heritable neurodegenerative disorder that is characterized by neuronal dysfunction and death, particularly in the cerebral cortex and medium spiny neurons of the striatum. This is followed by progressive chorea, dementia and emotional dysfunction, eventually resulting in death. HD is caused by an expanded CAG repeat in the first exon of the HD gene that results in an abnormally elongated polyQ (polyglutamine) tract in its protein product, Htt (Huntingtin). Wild-type Htt is largely cytoplasmic; however, in HD, proteolytic N-terminal fragments of Htt form insoluble deposits in both the cytoplasm and nucleus, provoking the idea that mutHtt (mutant Htt) causes transcriptional dysfunction. While a number of specific transcription factors and co-factors have been proposed as mediators of mutHtt toxicity, the causal relationship between these Htt/transcription factor interactions and HD pathology remains unknown. Previous work has highlighted REST [RE1 (repressor element 1)-silencing transcription factor] as one such transcription factor. REST is a master regulator of neuronal genes, repressing their expression. Many of its direct target genes are known or suspected to have a role in HD pathogenesis, including BDNF (brain-derived neurotrophic factor). Recent evidence has also shown that REST regulates transcription of regulatory miRNAs (microRNAs), many of which are known to regulate neuronal gene expression and are dysregulated in HD. Thus repression of miRNAs constitutes a second, indirect mechanism by which REST can alter the neuronal transcriptome in HD. We will describe the evidence that disruption to the REST regulon brought about by a loss of interaction between REST and mutHtt may be a key contributory factor in the widespread dysregulation of gene expression in HD.

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