title: 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.
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America ; Graduate Program in Genetics and Genomics, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Hoss
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America ; Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Kartha
authors.affiliation: Program in Bioinformatics and Integrative Biology, and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Jeanne C
authors.initials: JC
authors.lastname: Latourelle
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dumitriu
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Tiffany C
authors.initials: TC
authors.lastname: Hadzi
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Marcy E
authors.initials: ME
authors.lastname: Macdonald
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Friedman Brain Institute, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
authors.affiliation: Program in Bioinformatics and Integrative Biology, and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America ; Genome Science Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
mesh_terms: D000818:Animals; D001344:Autopsy; D002454:Cell Differentiation / Q000235:genetics*; D005786:Gene Expression Regulation; D005801:Genes, Homeobox; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000166:cytology; D018696:Neuroprotective Agents; D016716:PC12 Cells; D017397:Prefrontal Cortex / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats
chemical_list: D035683:MicroRNAs; D018696:Neuroprotective Agents; D012333:RNA, Messenger