title: Evidence for Epigenetic Regulation of Gene Expression and Function in Chronic Experimental Diabetic Neuropathy.
abstract: Diabetic polyneuropathy (DPN) is a common but irreversible neurodegenerative complication of diabetes mellitus. Here we show that features of sensory neuron damage in mice with chronic DPN may have altered epigenetic micro RNA (miRNA) transcriptional control. We profiled sensory neuron messenger RNA and miRNA profiles in mice with type I diabetes mellitus and findings of DPN. Diabetic sensory dorsal root ganglia neurons showed a pattern of altered messenger RNA profiles associated with upregulated cytoplasmic sites of miRNA-mediated messenger RNA processing (GW/P bodies). Dorsal root ganglia miRNA microarray identified significant changes in expression among mice with diabetes, the most prominent of which were a 39% downregulation of mmu-let-7i and a 255% increase in mmu-miR-341; both were identified in sensory neurons. To counteract these alterations, we replenished let-7i miRNA by intranasal administration; in a separate experiment, we added an anti-miR that antagonized elevated mmu-341 after 5 months of diabetes. Both approaches independently improved electrophysiologic, structural, and behavioral abnormalities without altering hyperglycemia; control sequences did not have these effects. Dissociated adult sensory neurons exposed to an exogenous mmu-let-7i mimic displayed enhanced growth and branching, indicating a trophic action. These findings identify roles for epigenetic miRNA alterations and enhanced GW/P expression in diabetic dorsal root ganglia that contribute to the complex DPN phenotype.
authors.affiliation: From the Division of Neurology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton (MK, DWZ); and Hotchkiss Brain Institute and Department of Clinical Neurosciences (CC, JAM, HN, VS, DWZ), Department of Anesthesia (JJM), Southern Alberta Microarray Facility (XW), and Department of Medicine (MJF), Faculty of Medicine, University of Calgary, Calgary, Canada.
authors.forename: Chu
authors.initials: C
authors.lastname: Cheng
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez
authors.forename: Hilarie
authors.initials: H
authors.lastname: Ng
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Moser
authors.forename: Xiuling
authors.initials: X
authors.lastname: Wang
authors.forename: Vandana
authors.initials: V
authors.lastname: Singh
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Fritzler
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Zochodne
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000235:genetics* / Q000503:physiopathology; D004594:Electrophysiology; D044127:Epigenesis, Genetic / Q000235:genetics*; D005727:Ganglia, Spinal / Q000503:physiopathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D035683:MicroRNAs