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

Hoss, Andrew G., Kartha, Vinay K., Dong, Xianjun, Latourelle, Jeanne C., Dumitriu, Alexandra, Hadzi, Tiffany C., MacDonald, Marcy E., Gusella, James F., Akbarian, Schahram, Chen, Jiang-Fan, Weng, Zhiping, Myers, Richard H.·2014·PLoS Genetics

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Figure 1 Differentially expressed miRNAs in Huntington's disease. miR-10b-5p, miR-1247-5p, miR-196a-5p, miR-196b-5p, and miR-615-3p were identified as differentially expressed in Huntington's disease prefrontal cortex compared to non-neurological disease controls by Illumina miRNA-sequencing. Normalized expression values quantified from DESeq analysis are shown on the y-axis. miR-196a-5p, miR-196b-5p and miR-615-3p were essentially not expressed in control samples, while the mean HD expression was 27.49, 11.01 and 6.66 respectively. miR-1247-5p was expressed at moderate levels in both control (mean = 49.44) and HD brain (mean = 102.01). miR-10b-5p was expressed in control (mean = 915.81) and highly expressed in HD brain (mean = 26,020.05). For miRNA, *p<0.05 and ***p<0.001, as determined by DESeq, followed by the Benjamini-Hochberg multiple comparison correction. (HD = Huntington's disease).
Figure 1 Differentially expressed miRNAs in Huntington's disease. miR-10b-5p, miR-1247-5p, miR-196a-5p, miR-196b-5p, and miR-615-3p were identified as differentially expressed in Huntington's disease prefrontal cortex compared to non-neurological disease controls by Illumina miRNA-sequencing. Normalized expression values quantified from DESeq analysis are shown on the y-axis. miR-196a-5p, miR-196b-5p and miR-615-3p were essentially not expressed in control samples, while the mean HD expression was 27.49, 11.01 and 6.66 respectively. miR-1247-5p was expressed at moderate levels in both control (mean = 49.44) and HD brain (mean = 102.01). miR-10b-5p was expressed in control (mean = 915.81) and highly expressed in HD brain (mean = 26,020.05). For miRNA, *p<0.05 and ***p<0.001, as determined by DESeq, followed by the Benjamini-Hochberg multiple comparison correction. (HD = Huntington's disease).CC BY · PubMed Central
Figure 2 miR-10b-5p expression in control, Parkinson's disease and Huntington's disease prefrontal cortex. Up-regulation of miR-10b-5p was confirmed in HD by performing RT-qPCR, comparing nineteen Huntington's disease prefrontal cortex samples to eighteen non-neurological disease control samples (***p<0.001) or fourteen Parkinson's disease samples (***p<0.001). ΔΔCT values of miR-10b-5p in PD and HD as compared to controls are shown on the y-axis. The absence of up-regulation in PD frontal cortex suggests that up-regulation of miR-10b-5p may be HD specific. (CT = cycle threshold; RT-qPCR = reverse transcription quantitative PCR; PD = Parkinson's disease; HD = Huntington's disease).
Figure 2 miR-10b-5p expression in control, Parkinson's disease and Huntington's disease prefrontal cortex. Up-regulation of miR-10b-5p was confirmed in HD by performing RT-qPCR, comparing nineteen Huntington's disease prefrontal cortex samples to eighteen non-neurological disease control samples (***p<0.001) or fourteen Parkinson's disease samples (***p<0.001). ΔΔCT values of miR-10b-5p in PD and HD as compared to controls are shown on the y-axis. The absence of up-regulation in PD frontal cortex suggests that up-regulation of miR-10b-5p may be HD specific. (CT = cycle threshold; RT-qPCR = reverse transcription quantitative PCR; PD = Parkinson's disease; HD = Huntington's disease).CC BY · PubMed Central
Figure 3 miR-10b-5p overexpressing PC12 Q73 cells exhibit reduced cytotoxicity. PC12 cells expressing huntingtin exon 1 with a polyglutamine expansion spanning 73 repeats were transfected with miR-10b-5p or cel-miR-67-3p as a negative control. On day 3 post-differentiation, a subset of cells were treated with 1 uM MG 132. A MTT assay was used to measure cell viability after four days post differentiation. On the Y-axis, the viability percentage was calculated from the initial cell count. Error bars represent SEM. (****p<0.0001; **p<0.001 *p<0.05).
Figure 3 miR-10b-5p overexpressing PC12 Q73 cells exhibit reduced cytotoxicity. PC12 cells expressing huntingtin exon 1 with a polyglutamine expansion spanning 73 repeats were transfected with miR-10b-5p or cel-miR-67-3p as a negative control. On day 3 post-differentiation, a subset of cells were treated with 1 uM MG 132. A MTT assay was used to measure cell viability after four days post differentiation. On the Y-axis, the viability percentage was calculated from the initial cell count. Error bars represent SEM. (****p<0.0001; **p<0.001 *p<0.05).CC BY · PubMed Central
Figure 4 Differentially expressed miRNAs in HD are located in Hox genes clusters. Schematic representation of Hox clusters. Hox genes are represented as numbered boxes (labeled 1–13), miRNA are represented by triangles and other genes in the regions (functional lncRNA, PRAC) are represented by rectangles. Antisense transcripts and pseudogenes are not pictured. Nineteen genes within Hox cluster regions were found significantly differentially expressed in HD prefrontal cortex using mRNA-sequencing (FDR-adjusted p-value<0.05). Four miRNAs, one lncRNA, and fourteen Hox genes were significantly up-regulated in HD (indicated by red), many of which are adjacent to differentially expressed miRNAs. A single Hox gene (HOXD1) was down-regulated in HD (indicated by blue). (HD = Huntington's disease).
Figure 4 Differentially expressed miRNAs in HD are located in Hox genes clusters. Schematic representation of Hox clusters. Hox genes are represented as numbered boxes (labeled 1–13), miRNA are represented by triangles and other genes in the regions (functional lncRNA, PRAC) are represented by rectangles. Antisense transcripts and pseudogenes are not pictured. Nineteen genes within Hox cluster regions were found significantly differentially expressed in HD prefrontal cortex using mRNA-sequencing (FDR-adjusted p-value<0.05). Four miRNAs, one lncRNA, and fourteen Hox genes were significantly up-regulated in HD (indicated by red), many of which are adjacent to differentially expressed miRNAs. A single Hox gene (HOXD1) was down-regulated in HD (indicated by blue). (HD = Huntington's disease).CC BY · PubMed Central

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Metadata

Authors
Hoss, A. G., Kartha, V. K., Dong, X., Latourelle, J. C., Dumitriu, A., Hadzi, T. C., MacDonald, M. E., Gusella, J. F., Akbarian, S., Chen, J.-F., Weng, Z., & Myers, R. H.
Venue
PLoS Genetics
Published
2014-02-27
Volume
10
Issue
2
Pages
e1004188
ISSN
1553-7404
Cited by
111
References
4
Language
en

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