MicroRNAs Located in the Hox Gene Clusters Are Implicated in Huntington's Disease Pathogenesis

Abstract

Transcriptional dysregulation has long been recognized as central to the pathogenesis of Huntington's disease (HD). MicroRNAs (miRNAs) represent a major system of post-transcriptional regulation, by either preventing translational initiation or by targeting transcripts for storage or for degradation. Using next-generation miRNA sequencing in prefrontal cortex (Brodmann Area 9) of twelve HD and nine controls, we identified five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-615-3p and miR-1247-5p) up-regulated in HD at genome-wide significance (FDR q-value<0.05). Three of these, miR-196a-5p, miR-196b-5p and miR-615-3p, were expressed at near zero levels in control brains. Expression was verified for all five miRNAs using reverse transcription quantitative PCR and all but miR-1247-5p were replicated in an independent sample (8HD/8C). Ectopic miR-10b-5p expression in PC12 HTT-Q73 cells increased survival by MTT assay and cell viability staining suggesting increased expression may be a protective response. All of the miRNAs but miR-1247-5p are located in intergenic regions of Hox clusters. Total mRNA sequencing in the same samples identified fifteen of 55 genes within the Hox cluster gene regions as differentially expressed in HD, and the Hox genes immediately adjacent to the four Hox cluster miRNAs as up-regulated. Pathway analysis of mRNA targets of these miRNAs implicated functions for neuronal differentiation, neurite outgrowth, cell death and survival. In regression models among the HD brains, huntingtin CAG repeat size, onset age and age at death were independently found to be inversely related to miR-10b-5p levels. CAG repeat size and onset age were independently inversely related to miR-196a-5p, onset age was inversely related to miR-196b-5p and age at death was inversely related to miR-615-3p expression. These results suggest these Hox-related miRNAs may be involved in neuroprotective response in HD. Recently, miRNAs have shown promise as biomarkers for human diseases and given their relationship to disease expression, these miRNAs are biomarker candidates in HD.

Genome of Rhodnius prolixus , an insect vector of Chagas disease, reveals unique adaptations to hematophagy and parasite infection

“…A3B) that was identified in one of the introns of the phosphatase-four-like protein gene (RPRC004331). The miRNA-target gene pairs also showed conservation; for example, rpr-miR-124-3p targeting the ROCK1 protein kinase gene (RPRC007732-RA) (14) and rpr-miR-10-3p targeting the Huntington-like gene (RPRC006430-RA) (15).…”

Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration

“…8). 20-30% of the PRC2-target genes that become up-regulated in PRC2-deficient MSNs, including Pou4f1/2, Hand2, Nkx2-5 , Twist1 , Tal1, Wt1 , and numerous Hox genes, significantly overlap with genes that are up-regulated in the postmortem human brains of HD patients 14,16,17 or HD mouse models 46,47 (Supplementary Fig. 8, Supplementary Table 7).…”

“…Moreover, the expression of mutant huntingtin in mouse ES cells or neuronal progenitor cells (NPCs) alters the pattern of genome-wide H3K27me3 distribution in both cell types 15 . The possible link between PRC2 and HD is further supported by the loss of neuronal PRC2/H3K27me3 sites 14 and the up-regulation of some of the PRC2 target genes in the HD affected human brain 14,16,17 . While these studies suggest that the PRC2 might represent a common target of different pathological processes that drive neurodegenerative diseases, the role of the PRC2 in the regulation of neuronal specification, function and survival in the adult brain is not known.…”

Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration

“…By contrast, expression of mutated Huntingtin protein in mouse ESCs or NPCs distorts genome-wide patterns of H3K27me3 together with a reduced presence of H3K4me3 at active loci [111]. The potential link between PRC2 and H3K4me3 is further supported by a significant depletion of H3K4me3 in HD-enriched peaks from ChIP-sequencing of neuronal chromatin from prefrontal cortices [109] and the upregulation of some inflammatory and developmental PRC2 target genes, particularly of certain Hox genes, in HD brains [112,113].…”