A myriad of miRNA variants in control and Huntington's disease brain regions detected by massively parallel sequencing.
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.
Martí
Eulàlia
E
Genetic Causes of Disease Group, Genes and Disease Program, Centre for Genomic Regulation (CRG), Catalonia, Spain. eulalia.marti@crg.es
Pantano
Lorena
L
Bañez-Coronel
Mónica
M
Llorens
Franc
F
Miñones-Moyano
Elena
E
Porta
Sílvia
S
Sumoy
Lauro
L
Ferrer
Isidre
I
Estivill
Xavier
X
D000328:Adult; D001921:Brain / Q000378:metabolism*; D005625:Frontal Lobe / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000737:chemistry* / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism; D058727:RNA, Small Untranslated / Q000737:chemistry; D012097:Repressor Proteins / Q000378:metabolism; D017423:Sequence Analysis, RNA; D000099229:RE1-Silencing Transcription Factor
D035683:MicroRNAs; D058727:RNA, Small Untranslated; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor