A myriad of miRNA variants in control and Huntington’s disease brain regions detected by massively parallel sequencing

Abstract

Huntington disease (HD) is a neurodegenerative disorder that predominantly affects neurons of the forebrain. We have applied the Illumina massively parallel sequencing to deeply analyze the small RNA populations of two different forebrain areas, the frontal cortex (FC) and the striatum (ST) of healthy individuals and individuals with HD. More than 80% of the small-RNAs were annotated as microRNAs (miRNAs) in all samples. Deep sequencing revealed length and sequence heterogeneity (IsomiRs) for the vast majority of miRNAs. Around 80–90% of the miRNAs presented modifications in the 3′-terminus mainly in the form of trimming and/or as nucleotide addition variants, while the 5′-terminus of the miRNAs was specially protected from changes. Expression profiling showed strong miRNA and isomiR expression deregulation in HD, most being common to both FC and ST. The analysis of the upstream regulatory regions in co-regulated miRNAs suggests a role for RE1-Silencing Transcription Factor (REST) and P53 in miRNAs downregulation in HD. The putative targets of deregulated miRNAs and seed-region IsomiRs strongly suggest that their altered expression contributes to the aberrant gene expression in HD. Our results show that miRNA variability is a ubiquitous phenomenon in the adult human brain, which may influence gene expression in physiological and pathological conditions.

Micro RNA -214,-150,-146a and-125b targetHuntingtingene

“…We don't know whether these miRNAs are altered in patients of HD, except for miR-146a, which is increased in HD patients. 12 We have shown earlier that expression of this miRNA is decreased in in STHdh Q111 /Hdh Q111 cells. These miRNAs together may alter many genes other than HTT and thus further studies are required using either human HD samples or animal models.…”

“…11 In high throughput RNA sequencing assay, it has been shown that 51 miRNAs are increased, while 35 miRNAs are decreased in the brains of HD patients. 12 A comprehensive list of miRNAs, altered in the postmortem brains of HD patients and HD models have been tabulated (Sup. Table 1).…”

“…Among these miRNAs, expression of miR-146a was increased in post mortem brains of HD patients, although it has not been validated further. 12 Regulation of HTT by miR-146a, miR-214, miR-125b and miR-150 thus may provide new insights into HD pathogenesis.…”

“…Also, it remains intriguing that the net effect of all the miRNAs which are biologically real targets on the expression of HTT is not known, the matter becomes more complex as the expression of miRNAs are altered in diseased state 7,10,12,40 and also as the miRNA expression shows spatial variation in tissues. But prior to answering this difficult part, it is important to validate real targets of miRNAs.…”

microRNA-Seq reveals cocaine-regulated expression of striatal microRNAs

“…Recent studies have demonstrated the importance of miRNAs in the pathophysiology of several neuropsychiatric disorders and mental retardation syndromes (Conrad et al 2010;Sulzer 2011), including schizophrenia (Burmistrova et al 2007;Beveridge et al 2010;Moreau et al 2011;Santarelli et al 2011), bipolar disorder, Fragile X mental retardation (Edbauer et al 2010;Krol et al 2010;Wulff et al 2011), Rett syndrome (Wu et al 2010), Alzheimer's disease, Parkinson's disease (Junn et al 2009), and Huntington's disease (Martí et al 2010). A number of the cocaine-responsive miRNAs identified in this study are important in controlling dendritic morphology; these miRNAs, and many others, may contribute to long-lasting forms of drugmediated synaptic plasticity through control of regulatory Lugli et al 2008 (adult mouse cortex and hippocampus; measured by microarray) with RNA-Seq data (adult mouse striatum) from these experiments (Lugli et al 2008).…”