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Gene Dysregulation in Huntington’s Disease: REST, MicroRNAs and Beyond

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Abstract

Huntington’s disease (HD) is an incurable, fatal neurodegenerative disorder that is caused by a polyglutamine expansion in the huntingtin (Htt) protein. Neuronal death in the striatum—the most obvious manifestation of the disease—is likely to result from widespread dysregulation of gene expression in various brain regions. To date, several potential mechanisms for this have been discovered, including one involving REST (RE1-Silencing Transcription Factor), a master regulator of neuronal genes. Recently, independent studies have demonstrated that post-transcriptional gene regulation by microRNAs is also disrupted in HD. Expression of key neuronal microRNAs—including mir-9/9*, mir-124 and mir-132—is repressed in the brains of human HD patients and mouse models. These changes occur downstream of REST, and are likely to result in major disruption of mRNA regulation and neuronal function. In this study we will discuss these findings and their implications for our understanding of HD. Using updated bioinformatic analysis, we predict 21 new candidate microRNAs in HD. We propose future strategies for unifying large-scale transcriptional and microRNA datasets with the aim of explaining HD aetiology. By way of example, we show how available genomic datasets can be integrated to provide independent, analytical validation for dysregulation of REST and microRNA mir-124 in HD. As a consequence, gene ontology analysis indicates that HD is characterised by a broad-based depression of neural genes in the caudate and motor cortex. Thus, we propose that a combination of REST, microRNAs and possibly other non-coding RNAs profoundly affect the neuronal transcriptome in HD.

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Abbreviations

HD:

Huntington’s disease

Htt:

Huntingtin

mutHtt:

Mutant huntingtin

BDNF:

Brain-derived neurotrophic factor

miRNA:

MicroRNA

REST:

Repressor element 1-silencing transcription factor

RE1:

Repressor element 1

NRSF:

Neuron-restrictive silencing factor

NRSE:

Neuron-restrictive silencing element

SCA:

Spinocerebellar ataxia

SP1:

Specificity protein 1

RISC:

RNA-induced silencing complex

DRPLA:

Dentatorubral-pallidoluysian atrophy

SBMA:

Spinobulbar muscular atrophy

MRE:

MicroRNA response element

CREB:

cAMP response element binding

MeCP2:

Methyl CpG binding protein 2

BACE1:

β-site of APP cleaving enzyme

AD:

Alzheimer’s disease

ncRNA:

Noncoding RNA

ChIP-Seq:

Chromatin immunoprecipitation coupled to high-throughput sequencing

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Acknowledgements

We wish to thank Chiara Zuccato (University of Milan), Andrew M. Thomson (Genome Institute of Singapore) and Lawrence W. Stanton (Genome Institute of Singapore) for advice, discussions and critical reading of the manuscript. RJ is a postdoctoral fellow funded by the Singapore Agency for Science, Technology and Research (A*STAR).

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  1. Stem Cell and Developmental Biology Group, Genome Institute of Singapore, 60 Biopolis Street, Singapore, 138672, Singapore

    Rory Johnson

  2. Centre for the Cellular Basis of Behaviour, Centre for Cell and Integrative Biology, King’s College London, Institute of Psychiatry, London, SE5 9NU, UK

    Noel J. Buckley

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Johnson, R., Buckley, N.J. Gene Dysregulation in Huntington’s Disease: REST, MicroRNAs and Beyond. Neuromol Med 11, 183–199 (2009). https://doi.org/10.1007/s12017-009-8063-4

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