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Transcription, epigenetics and ameliorative strategies in Huntington's Disease: a genome-wide perspective.

Valor LM - Mol. Neurobiol. (2014)

Bottom Line: Although still incipient, the introduction of combined next-generation sequencing techniques is enhancing our comprehension of the mechanisms underlying altered transcriptional dysregulation in HD by providing the first genomic landscapes associated with epigenetics and the occupancy of transcription factors.In addition, the use of genome-wide approaches is becoming more and more necessary to evaluate the efficacy and safety of ameliorative strategies and to identify novel mechanisms of amelioration that may help in the improvement of current preclinical therapeutics.Finally, the major conclusions obtained from HD transcriptomics studies have the potential to be extrapolated to other neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, Av. Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550, Alicante, Spain, lmv@umh.es.

ABSTRACT
Transcriptional dysregulation in Huntington's disease (HD) is an early event that shapes the brain transcriptome by both the depletion and ectopic activation of gene products that eventually affect survival and neuronal functions. Disruption in the activity of gene expression regulators, such as transcription factors, chromatin-remodeling proteins, and noncoding RNAs, accounts for the expression changes observed in multiple animal and cellular models of HD and in samples from patients. Here, I review the recent advances in the study of HD transcriptional dysregulation and its causes to finally discuss the possible implications in ameliorative strategies from a genome-wide perspective. To date, the use of genome-wide approaches, predominantly based on microarray platforms, has been successful in providing an extensive catalog of differentially regulated genes, including biomarkers aimed at monitoring the progress of the pathology. Although still incipient, the introduction of combined next-generation sequencing techniques is enhancing our comprehension of the mechanisms underlying altered transcriptional dysregulation in HD by providing the first genomic landscapes associated with epigenetics and the occupancy of transcription factors. In addition, the use of genome-wide approaches is becoming more and more necessary to evaluate the efficacy and safety of ameliorative strategies and to identify novel mechanisms of amelioration that may help in the improvement of current preclinical therapeutics. Finally, the major conclusions obtained from HD transcriptomics studies have the potential to be extrapolated to other neurodegenerative disorders.

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Related in: MedlinePlus

Summary of the gene profiling and other genome-wide studies in HD. The graph represents the number of studies per publication year with the most relevant milestones in the field of HD transcriptional dysregulation. Note that a few studies may contain more than one approach, categorized as “Array” (expression and ChIP-on-chip), “NGS” (next-generation sequencing, RNA-seq, ChIP-seq, sequencing of methylated DNA) and “Others” (PCR-based: differential display, adapter-tagged competitive PCR, panels). Reports with solely reanalysis (i.e., without generating data de novo) or chemically lesioned striatal models are not considered. References per year: 2000, [22]; 2001, [10, 15]; 2002: [12, 23, 24, 31, 65]; 2003, [173, 193]; 2004, [11]; 2005, [9, 25, 51, 135, 159, 194]; 2006, [26, 34, 36, 37, 157, 195]; 2007, [32, 38, 52, 54, 72, 110, 133, 154, 196]; 2008, [13, 27, 33, 39, 56, 103, 125, 155]; 2009, [35, 151, 152, 197]; 2010, [14, 16, 158, 165, 174, 192]; 2011, [18, 19, 30, 50, 57, 67, 119, 127, 156, 198]; 2012, [17, 66, 99, 111, 112, 181, 199]; 2013, [20, 21, 28, 29, 49, 53, 68, 113, 116, 124, 128, 180, 200]
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Fig1: Summary of the gene profiling and other genome-wide studies in HD. The graph represents the number of studies per publication year with the most relevant milestones in the field of HD transcriptional dysregulation. Note that a few studies may contain more than one approach, categorized as “Array” (expression and ChIP-on-chip), “NGS” (next-generation sequencing, RNA-seq, ChIP-seq, sequencing of methylated DNA) and “Others” (PCR-based: differential display, adapter-tagged competitive PCR, panels). Reports with solely reanalysis (i.e., without generating data de novo) or chemically lesioned striatal models are not considered. References per year: 2000, [22]; 2001, [10, 15]; 2002: [12, 23, 24, 31, 65]; 2003, [173, 193]; 2004, [11]; 2005, [9, 25, 51, 135, 159, 194]; 2006, [26, 34, 36, 37, 157, 195]; 2007, [32, 38, 52, 54, 72, 110, 133, 154, 196]; 2008, [13, 27, 33, 39, 56, 103, 125, 155]; 2009, [35, 151, 152, 197]; 2010, [14, 16, 158, 165, 174, 192]; 2011, [18, 19, 30, 50, 57, 67, 119, 127, 156, 198]; 2012, [17, 66, 99, 111, 112, 181, 199]; 2013, [20, 21, 28, 29, 49, 53, 68, 113, 116, 124, 128, 180, 200]

Mentions: A long list of gene expression datasets have been generated in less than 15 years of research on multiple HD animal and cellular models and, importantly, on postmortem material from patients (Fig. 1). The preferred system for the analysis of HD transcriptomics has been microarray technology, with some studies using alternative approaches, such as differential display transcription [10, 11], to capture novel changing genes not represented by the arrays at the time, or systematic qPCR-based assays [12–15], to selectively interrogate specific subsets of genes with high sensitivity as in the case of microRNAs (miRNAs), prior to the use of dedicated microarrays and deep sequencing technologies [16–19]. The results obtained using the most novel RNA-seq approach are consistent with microarray-based profiles [16, 20, 21], with the added benefit that they analyze the behavior of poorly characterized gene products, such as variants of mature miRNA or isomiRs [16].Fig. 1


Transcription, epigenetics and ameliorative strategies in Huntington's Disease: a genome-wide perspective.

Valor LM - Mol. Neurobiol. (2014)

Summary of the gene profiling and other genome-wide studies in HD. The graph represents the number of studies per publication year with the most relevant milestones in the field of HD transcriptional dysregulation. Note that a few studies may contain more than one approach, categorized as “Array” (expression and ChIP-on-chip), “NGS” (next-generation sequencing, RNA-seq, ChIP-seq, sequencing of methylated DNA) and “Others” (PCR-based: differential display, adapter-tagged competitive PCR, panels). Reports with solely reanalysis (i.e., without generating data de novo) or chemically lesioned striatal models are not considered. References per year: 2000, [22]; 2001, [10, 15]; 2002: [12, 23, 24, 31, 65]; 2003, [173, 193]; 2004, [11]; 2005, [9, 25, 51, 135, 159, 194]; 2006, [26, 34, 36, 37, 157, 195]; 2007, [32, 38, 52, 54, 72, 110, 133, 154, 196]; 2008, [13, 27, 33, 39, 56, 103, 125, 155]; 2009, [35, 151, 152, 197]; 2010, [14, 16, 158, 165, 174, 192]; 2011, [18, 19, 30, 50, 57, 67, 119, 127, 156, 198]; 2012, [17, 66, 99, 111, 112, 181, 199]; 2013, [20, 21, 28, 29, 49, 53, 68, 113, 116, 124, 128, 180, 200]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig1: Summary of the gene profiling and other genome-wide studies in HD. The graph represents the number of studies per publication year with the most relevant milestones in the field of HD transcriptional dysregulation. Note that a few studies may contain more than one approach, categorized as “Array” (expression and ChIP-on-chip), “NGS” (next-generation sequencing, RNA-seq, ChIP-seq, sequencing of methylated DNA) and “Others” (PCR-based: differential display, adapter-tagged competitive PCR, panels). Reports with solely reanalysis (i.e., without generating data de novo) or chemically lesioned striatal models are not considered. References per year: 2000, [22]; 2001, [10, 15]; 2002: [12, 23, 24, 31, 65]; 2003, [173, 193]; 2004, [11]; 2005, [9, 25, 51, 135, 159, 194]; 2006, [26, 34, 36, 37, 157, 195]; 2007, [32, 38, 52, 54, 72, 110, 133, 154, 196]; 2008, [13, 27, 33, 39, 56, 103, 125, 155]; 2009, [35, 151, 152, 197]; 2010, [14, 16, 158, 165, 174, 192]; 2011, [18, 19, 30, 50, 57, 67, 119, 127, 156, 198]; 2012, [17, 66, 99, 111, 112, 181, 199]; 2013, [20, 21, 28, 29, 49, 53, 68, 113, 116, 124, 128, 180, 200]
Mentions: A long list of gene expression datasets have been generated in less than 15 years of research on multiple HD animal and cellular models and, importantly, on postmortem material from patients (Fig. 1). The preferred system for the analysis of HD transcriptomics has been microarray technology, with some studies using alternative approaches, such as differential display transcription [10, 11], to capture novel changing genes not represented by the arrays at the time, or systematic qPCR-based assays [12–15], to selectively interrogate specific subsets of genes with high sensitivity as in the case of microRNAs (miRNAs), prior to the use of dedicated microarrays and deep sequencing technologies [16–19]. The results obtained using the most novel RNA-seq approach are consistent with microarray-based profiles [16, 20, 21], with the added benefit that they analyze the behavior of poorly characterized gene products, such as variants of mature miRNA or isomiRs [16].Fig. 1

Bottom Line: Although still incipient, the introduction of combined next-generation sequencing techniques is enhancing our comprehension of the mechanisms underlying altered transcriptional dysregulation in HD by providing the first genomic landscapes associated with epigenetics and the occupancy of transcription factors.In addition, the use of genome-wide approaches is becoming more and more necessary to evaluate the efficacy and safety of ameliorative strategies and to identify novel mechanisms of amelioration that may help in the improvement of current preclinical therapeutics.Finally, the major conclusions obtained from HD transcriptomics studies have the potential to be extrapolated to other neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, Av. Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550, Alicante, Spain, lmv@umh.es.

ABSTRACT
Transcriptional dysregulation in Huntington's disease (HD) is an early event that shapes the brain transcriptome by both the depletion and ectopic activation of gene products that eventually affect survival and neuronal functions. Disruption in the activity of gene expression regulators, such as transcription factors, chromatin-remodeling proteins, and noncoding RNAs, accounts for the expression changes observed in multiple animal and cellular models of HD and in samples from patients. Here, I review the recent advances in the study of HD transcriptional dysregulation and its causes to finally discuss the possible implications in ameliorative strategies from a genome-wide perspective. To date, the use of genome-wide approaches, predominantly based on microarray platforms, has been successful in providing an extensive catalog of differentially regulated genes, including biomarkers aimed at monitoring the progress of the pathology. Although still incipient, the introduction of combined next-generation sequencing techniques is enhancing our comprehension of the mechanisms underlying altered transcriptional dysregulation in HD by providing the first genomic landscapes associated with epigenetics and the occupancy of transcription factors. In addition, the use of genome-wide approaches is becoming more and more necessary to evaluate the efficacy and safety of ameliorative strategies and to identify novel mechanisms of amelioration that may help in the improvement of current preclinical therapeutics. Finally, the major conclusions obtained from HD transcriptomics studies have the potential to be extrapolated to other neurodegenerative disorders.

Show MeSH
Related in: MedlinePlus