Genome-wide loss of 5-hmC is a novel epigenetic feature of Huntington's disease
| Autor: | Fengli Wang, Xiwen Lin, You-Qi Liao, Wenjuan Xie, Dandan Wang, Shu Zhu, Tie-Shan Tang, Caixia Guo, Qinmiao Sun, Huai-Rong Luo, Jiu-Qiang Wang, Yun-Gui Yang, Chunsheng Han, Yeran Yang, Yong-Sheng Wu |
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| Rok vydání: | 2013 |
| Předmět: |
Epigenomics
Transgene Mice Transgenic Nerve Tissue Proteins Biology Cytosine Mice Huntington's disease Genetics medicine Animals Humans Epigenetics Molecular Biology Genetics (clinical) Glutamate receptor Wnt signaling pathway Brain Sequence Analysis DNA General Medicine DNA Methylation medicine.disease Corpus Striatum Cell biology Disease Models Animal Huntington Disease DNA methylation 5-Methylcytosine Signal transduction Sequence Alignment |
| Zdroj: | Human Molecular Genetics. 22:3641-3653 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddt214 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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