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Huntingtons disease (HD) is an inherited, fatal neurodegenerative disorder characterized by the progressive loss of striatal medium spiny neurons.HD is caused by the expanded polyglutamine (polyQ) stretch in the amino-terminus of huntingtin protein (HTT), a 350 kDa ubiquitously expressed protein of unknown function.The exact mechanism(s) underlying the cause of neurodegeneration in HD remain obscure.Objective 5-hydroxymethylcytosine (5-hmC) may represent a new epigenetic modification of cytosine.While the dynamics of 5-hrnC during neurodevelopment have recently been reported, little is known about its genomic distribution and function(s) in neurodegenerative diseases such as Huntingtons disease (HD).Methods To gain a genome-wide view of 5-hmC distribution, we employed a 5-hmC-specific chemical labeling and enrichment technology coupled with high-throughput deep sequencing of 5-hmC-containing DNA fragments.Striatal and cortical DNA samples from the brains of 3-month-old WT/YAC 128 mice were prepared and deeply sequenced to determine the effect of HTTexp on the 5-hmC epigenome at the early stage of HD.Results We generated first genome-wide maps of 5-hmC in striatum and cortex from both WT and YAC128 HD mice brains, and we observed a marked reduction of 5-hmC signal in YAC128 HD mouse brain tissues.General genomic features of 5-hmC are highly conserved, not being affected by either disease or brain regions.We have identified disease-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 of genotype-specific DhMR-annotated genes revealed that alternation of a number of canonical pathways involving neuronal development/differentiation (Wnt/-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.Conclusion Our results indicate that genome-wide loss of the 5-hmC marker is a novel epigenetic feature in Huntingtons Disease, and that this aberrant epigenetic regulation may impair the neurogenesis, neuronal function and survival in HD brain.The Aberrant Ca2+ Signaling and 5-hmC epigenome may be functionally interacted to initiate HD pathology.Our results also suggest that targeting mitochondrial Ca2+ and 5-hmC epigenome could be therapeutic strategies for HD.