Genome-wide loss of 5-hmC is a novel epigenetic feature of huntington's disease

Abstract

5-Hydroxymethylcytosine (5-hmC)mayrepresent anewepigeneticmodification of cytosine. While thedynamics of 5-hmC during neurodevelopment have recently been reported, little is known about its genomic distribution and function(s) in neurodegenerative diseases such as Huntington's disease (HD).We here observed a marked reduction of the 5-hmC signal in YAC128 (yeast artificial chromosome transgenewith 128 CAG repeats) HDmouse brain tissueswhencomparedwith age-matched wild-type (WT) mice, suggestingadeficiencyof 5-hmCreconstructionin HDbrains duringpostnatal development. Genome-wide distributionanalysisof5-hmCfurtherconfirmedthediminishment of the 5-hmC signal in striatum and cortex in YAC128 HD mice. General genomic features of 5-hmC are highlyconserved, notbeingaffectedbyeitherdiseaseor brain regions. Intriguingly, wehaveidentifieddisease-specific (YAC128 versus WT) differentially hydroxymethylated regions (DhMRs), and found that acquisition of DhmRs in gene body is a positive epigenetic regulator for gene expression. Ingenuity pathway analysis (IPA) of genotypespecificDhMR- annotatedgenesrevealedthatalternationofanumberofcanonicalpathwaysinvolvingneuronaldevelopment/differentiation (Wnt/b-catenin/Sox pathway, axonal guidance signaling pathway) and neuronal function/survival (glutamate receptor/calcium/CREB, GABA receptor signaling, dopamine-DARPP32 feedback pathway, etc.) could be important for the onset of HD. Our results indicate that loss of the 5-hmC marker is a novel epigenetic feature in HD, and that this aberrant epigenetic regulationmay impair the neurogenesis, neuronal function and survival in HD brain. Our study also opens a new avenue for HD treatment; re-establishing the native 5-hmC landscapemay have the potential to slow/halt the progression of HD. © The Author 2013. Published by Oxford University Press. All rights reserved.