title: Genome-wide loss of 5-hmC is a novel epigenetic feature of Huntington's disease.
abstract: 5-Hydroxymethylcytosine (5-hmC) may represent a new epigenetic modification of cytosine. While the dynamics 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 transgene with 128 CAG repeats) HD mouse brain tissues when compared with age-matched wild-type (WT) mice, suggesting a deficiency of 5-hmC reconstruction in HD brains during postnatal development. Genome-wide distribution analysis of 5-hmC further confirmed the diminishment of the 5-hmC signal in striatum and cortex in YAC128 HD mice. General genomic features of 5-hmC are highly conserved, not being affected by either disease or brain regions. Intriguingly, 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 (IPA) of genotype-specific DhMR-annotated genes revealed that alternation of a number of canonical pathways involving neuronal development/differentiation (Wnt/β-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 regulation may 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 landscape may have the potential to slow/halt the progression of HD.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing, China.
authors.forename: Fengli
authors.initials: F
authors.lastname: Wang
authors.forename: Yeran
authors.initials: Y
authors.lastname: Yang
authors.forename: Xiwen
authors.initials: X
authors.lastname: Lin
authors.forename: Jiu-Qiang
authors.initials: JQ
authors.lastname: Wang
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Wu
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Xie
authors.forename: Dandan
authors.initials: D
authors.lastname: Wang
authors.forename: Shu
authors.initials: S
authors.lastname: Zhu
authors.forename: You-Qi
authors.initials: YQ
authors.lastname: Liao
authors.forename: Qinmiao
authors.initials: Q
authors.lastname: Sun
authors.forename: Yun-Gui
authors.initials: YG
authors.lastname: Yang
authors.forename: Huai-Rong
authors.initials: HR
authors.lastname: Luo
authors.forename: Caixia
authors.initials: C
authors.lastname: Guo
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Han
authors.forename: Tie-Shan
authors.initials: TS
authors.lastname: Tang
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D057890:Epigenomics; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D009419:Nerve Tissue Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine